ORCID Profile
0000-0003-0498-1910
Current Organisation
La Trobe University
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Biochemistry and Cell Biology | Medical Biochemistry: Proteins And Peptides | Bioinformatics Software | Biochemistry And Cell Biology Not Elsewhere Classified | Medicinal and Biomolecular Chemistry | Macromolecular and Materials Chemistry | Quantum Chemistry | Cheminformatics and Quantitative Structure-Activity Relationships | Nanochemistry and Supramolecular Chemistry | Theory and Design of Materials | Receptors and Membrane Biology | Nanoscale Characterisation | Structural Biology (incl. Macromolecular Modelling) | Biological Physics | Condensed Matter Physics not elsewhere classified | Turbulent Flows | Genomics | Medical Biochemistry and Metabolomics | Theoretical and Computational Chemistry not elsewhere classified | Nanotechnology | Cell Development (Incl. Cell Division And Apoptosis) | Interdisciplinary Engineering | Medical And Health Sciences Not Elsewhere Classified | Nanobiotechnology
ANZSRC Socio-Economic Objective (SEO)
Expanding Knowledge in the Chemical Sciences | Expanding Knowledge in the Physical Sciences | Expanding Knowledge in the Biological Sciences | Treatments (e.g. chemicals, antibiotics) | Health related to ageing | Human Diagnostics | Cancer and related disorders | Biological sciences | Expanding Knowledge in the Medical and Health Sciences | Expanding Knowledge in Engineering | Expanding Knowledge in the Information and Computing Sciences |
Related Links
Publications
A newly discovered protein export machine in malaria parasites
Publisher: Springer Science and Business Media LLC
Date: 06-2009
DOI: 10.1038/NATURE08104
Potential energy surfaces describing ion complexes containing molecular hydrogen
Publisher: AIP Publishing
Date: 15-07-1992
DOI: 10.1063/1.463246
Abstract: High-level ab initio molecular orbital calculations have been carried out to describe the potential energy surfaces for a series of systems corresponding formally to dimer ions of molecular hydrogen with an inert-gas atom or a first- or second-row hydride [X⋅⋅⋅H2]̇ +, where X=He, Ne, Ar, Kr, HF, HCl, H2O, H2S, NH3, and PH3. Of the [XH2]̇ + ion complexes, [Ne⋅⋅⋅H2]̇ +, [Ar⋅⋅⋅H2]̇ +, [Kr⋅⋅⋅H2]̇ +, and [HFH⋅⋅⋅H]̇ + lie in wells of significant depth and should be experimentally observable. The energetics of ion–molecule reactions associated with the [XH2]̇ + systems have been examined in detail. The reactions include proton- and hydrogen-transfer reactions and hydrogen-exchange reactions. Pathways and transition structures for scrambling of hydrogen atoms within the [XH2]̇ + complexes, some of which are relevant to the exchange reactions, have also been determined.
Discovery of Inhibitors of Lupin Diadenosine 5′,5′′′-P1,P4-Tetraphosphate Hydrolase by Virtual Screening
Publisher: American Chemical Society (ACS)
Date: 23-07-2009
DOI: 10.1021/BI900813X
Abstract: Novel inhibitors of lupin diadenosine 5',5'''-P(1),P(4)-tetraphosphate (Ap(4)A) hydrolase have been identified by in silico screening of a large virtual chemical library. Compounds were ranked on the basis of a consensus from six scoring functions. From the top 100 ranked compounds six were selected and initially screened for inhibitory activity using a single concentration isothermal titration calorimetry assay. Two of these compounds that showed excellent solubility properties were further analyzed, but only one [NSC51531 2-((8-hydroxy-4-(4-methyl-2-sulfoanilino)-9,10-dioxo-9,10-dihydro-1-anthracenyl)amino)-5-methylbenzenesulfonic acid] exhibited competitive inhibition with a K(i) of 1 microM. A structural analogue of this compound also exhibited competitive inhibition with a comparable K(i) of 2.9 microM. (1)H, (15)N NMR spectroscopy was used to map the binding site of NSC51531 on lupin Ap(4)A hydrolase and demonstrated that the compound bound specifically in the substrate-binding site, consistent with the competitive inhibition results. Binding of NSC51531 to the human form of Ap(4)A hydrolase is nonspecific, suggesting that this compound may represent a useful lead in the design of specific inhibitors of the plant-like form of Ap(4)A hydrolases.
Letter to the Editor: 1H, 13C, and 15N resonance assignments of the 17 kDa Ap4A hydrolase from Homo sapiens in the presence and absence of ATP
Publisher: Springer Science and Business Media LLC
Date: 02-2005
Structure of the Analgesic μ-Conotoxin KIIIA and Effects on the Structure and Function of Disulfide Deletion
Publisher: American Chemical Society (ACS)
Date: 26-01-2009
DOI: 10.1021/BI801998A
Pseudohypoaldosteronism type 1: the index case revisited
Publisher: Wiley
Date: 08-02-2011
A Six-Week Trial of Hula Hooping Using a Weighted Hoop
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2015
Calculation of Proton Affinities Using the G2(MP2,SVP) Procedure
Publisher: American Chemical Society (ACS)
Date: 04-1995
DOI: 10.1021/J100017A028
Heat of Formation of the tert-Butyl Radical
Publisher: American Chemical Society (ACS)
Date: 12-1998
DOI: 10.1021/JP9826470
Inhibition of Plasmepsin V Activity Demonstrates Its Essential Role in Protein Export, PfEMP1 Display, and Survival of Malaria Parasites
Publisher: Public Library of Science (PLoS)
Date: 07-2014
Catalytic Mechanisms and Reaction Intermediates along the Hydrolytic Pathway of a Plant β-D-glucan Glucohydrolase
Publisher: Elsevier BV
Date: 11-2001
DOI: 10.1016/S0969-2126(01)00673-6
Abstract: Barley beta-D-glucan glucohydrolases represent family 3 glycoside hydrolases that catalyze the hydrolytic removal of nonreducing glucosyl residues from beta-D-glucans and beta-D-glucooligosaccharides. After hydrolysis is completed, glucose remains bound in the active site. When conduritol B epoxide and 2', 4'-dinitrophenyl 2-deoxy-2-fluoro-beta-D-glucopyranoside are diffused into enzyme crystals, they displace the bound glucose and form covalent glycosyl-enzyme complexes through the Odelta1 of D285, which is thereby identified as the catalytic nucleophile. A nonhydrolyzable S-glycosyl analog, 4(I), 4(III), 4(V)-S-trithiocellohexaose, also diffuses into the active site, and a S-cellobioside moiety positions itself at the -1 and +1 subsites. The glycosidic S atom of the S-cellobioside moiety forms a short contact (2.75 A) with the Oepsilon2 of E491, which is likely to be the catalytic acid/base. The glucopyranosyl residues of the S-cellobioside moiety are not distorted from the low-energy 4C(1) conformation, but the glucopyranosyl ring at the +1 subsite is rotated and translated about the linkage. X-ray crystallography is used to define the three key intermediates during catalysis by beta-D-glucan glucohydrolase. Before a new hydrolytic event begins, the bound product (glucose) from the previous catalytic reaction is displaced by the incoming substrate, and a new enzyme-substrate complex is formed. The second stage of the hydrolytic pathway involves glycosidic bond cleavage, which proceeds through a double-displacement reaction mechanism. The crystallographic analysis of the S-cellobioside-enzyme complex with quantum mechanical modeling suggests that the complex might mimic the oxonium intermediate rather than the enzyme-substrate complex.
Changes in Essential Fatty Acids and Ileal Genes Associated with Metabolizing Enzymes and Fatty Acid Transporters in Rodent Models of Cystic Fibrosis
Publisher: MDPI AG
Date: 13-04-2023
DOI: 10.3390/IJMS24087194
Abstract: Cystic fibrosis (CF), the result of mutations in the CF transmembrane conductance regulator (CFTR), causes essential fatty acid deficiency. The aim of this study was to characterize fatty acid handling in two rodent models of CF one strain which harbors the loss of phenylalanine at position 508 (Phe508del) in CFTR and the other lacks functional CFTR (510X). Fatty acid concentrations were determined using gas chromatography in serum from Phe508del and 510X rats. The relative expression of genes responsible for fatty acid transport and metabolism were quantified using real-time PCR. Ileal tissue morphology was assessed histologically. There was an age-dependent decrease in eicosapentaenoic acid and the linoleic acid:α-linolenic acid ratio, a genotype-dependent decrease in docosapentaenoic acid (n-3) and an increase in the arachidonic acid:docosahexaenoic acid ratio in Phe508del rat serum, which was not observed in 510X rats. In the ileum, Cftr mRNA was increased in Phe508del rats but decreased in 510X rats. Further, Elvol2, Slc27a1, Slc27a2 and Got2 mRNA were increased in Phe508del rats only. As assessed by Sirius Red staining, collagen was increased in Phe508del and 510X ileum. Thus, CF rat models exhibit alterations in the concentration of circulating fatty acids, which may be due to altered transport and metabolism, in addition to fibrosis and microscopic structural changes in the ileum.
Entropies and Free Energies of Protonation and Proton-Transfer Reactions
Publisher: American Chemical Society (ACS)
Date: 09-1997
DOI: 10.1021/JA970891J
Structure-Guided Rescaffolding of Selective Antagonists of BCL-XL
Publisher: American Chemical Society (ACS)
Date: 31-03-2014
DOI: 10.1021/ML500030P
Modelling the structure of the fusion protein from human respiratory syncytial virus
Publisher: Oxford University Press (OUP)
Date: 05-2002
Abstract: The fusion protein of respiratory syncytial virus (RSV-F) is responsible for fusion of virion with host cells and infection of neighbouring cells through the formation of syncytia. A three-dimensional model structure of RSV-F was derived by homology modelling from the structure of the equivalent protein in Newcastle disease virus (NDV). Despite very low sequence homology between the two structures, most features of the model appear to have high credibility, although a few small regions in RSV-F whose secondary structure is predicted to be different to that in NDV are likely to be poorly modelled. The organization of in idual residues identified in escape mutants against monoclonal antibodies correlates well with known antigenic sites. The location of residues involved in point mutations in several drug-resistant variants is also examined.
Assigning absolute values to proton affinities: a differentiation between competing scales
Publisher: American Chemical Society (ACS)
Date: 06-1993
DOI: 10.1021/JA00064A058
Conversion of Bim-BH3 from Activator to Inhibitor of Bak through Structure-Based Design
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.MOLCEL.2017.11.001
Abstract: Certain BH3-only proteins transiently bind and activate Bak and Bax, initiating their oligomerization and the permeabilization of the mitochondrial outer membrane, a pivotal step in the mitochondrial pathway to apoptosis. Here we describe the first crystal structures of an activator BH3 peptide bound to Bak and illustrate their use in the design of BH3 derivatives capable of inhibiting human Bak on mitochondria. These BH3 derivatives compete for the activation site at the canonical groove, are the first engineered inhibitors of Bak activation, and support the role of key conformational transitions associated with Bak activation.
The vinylidene-acetylene rearrangement. A phantom minimum on the MP2 potential energy surface
Publisher: Elsevier BV
Date: 1992
Structure of the BAK-activating antibody 7D10 bound to BAK reveals an unexpected role for the α1-α2 loop in BAK activation
Publisher: Springer Science and Business Media LLC
Date: 12-03-2022
Conformational Changes in Bcl-2 Pro-survival Proteins Determine Their Capacity to Bind Ligands
Publisher: Elsevier BV
Date: 10-2009
The D-Diastereomer of ShK Toxin Selectively Blocks Voltage-gated K+ Channels and Inhibits T Lymphocyte Proliferation
Publisher: Elsevier BV
Date: 2008
Heats of Formation of Alkali and Alkaline Earth Oxides and Hydroxides: Some Dramatic Failures of the G2 Method
Publisher: American Chemical Society (ACS)
Date: 31-08-1999
DOI: 10.1021/JP991577+
Bak apoptotic pores involve a flexible C-terminal region and juxtaposition of the C-terminal transmembrane domains
Publisher: Springer Science and Business Media LLC
Date: 06-03-2015
DOI: 10.1038/CDD.2015.15
Predicting aqueous solubility by QSPR modeling
Publisher: Elsevier BV
Date: 07-2021
Anticonvulsant Met-Enkephalin Analogues Containing Backbone Spacers Reveal Alternative Non-Opioid Signaling in the Brain
Publisher: American Chemical Society (ACS)
Date: 27-07-2009
DOI: 10.1021/CB900045C
Abstract: Prosthesis of non-critical parts of a polypeptide backbone is an attractive strategy to simplify bioactive peptides. This approach was applied to an opioid neuropeptide, Met-enkephalin, in which two adjacent Gly2-Gly3 residues were replaced with a series of non-peptidic backbone spacers varying in length and/or physicochemical properties. The backbone spacers did not affect the overall structural properties of the analogues, but they did dramatically reduce their affinities and agonist activities toward delta- and mu-opioid receptors. Molecular modeling suggested that the decrease of the affinity of Met-enkephalin to delta-opioid receptor could be accounted for by the loss of a single hydrogen bond. Remarkably, the analogues containing the most isostere spacers retained potent antinociceptive and anticonvulsant properties that were comparable to that of the endogenous peptide. This unexpected high in vivo potency could not be accounted for by an increase in metabolic stability. Moreover, the antiepileptic activity could not be reversed by opioid receptor antagonists. In summary, the results obtained with the analogues containing backbone spacers suggest a novel mechanism for seizure control in the brain that involves alternative non-opioid signaling.
Structure of glyceraldehyde-3-phosphate dehydrogenase fromPlasmodium falciparum
Publisher: International Union of Crystallography (IUCr)
Date: 16-08-2005
Bax Crystal Structures Reveal How BH3 Domains Activate Bax and Nucleate Its Oligomerization to Induce Apoptosis
Publisher: Elsevier BV
Date: 2013
DOI: 10.1016/J.CELL.2012.12.031
Abstract: In stressed cells, apoptosis ensues when Bcl-2 family members Bax or Bak oligomerize and permeabilize the mitochondrial outer membrane. Certain BH3-only relatives can directly activate them to mediate this pivotal, poorly understood step. To clarify the conformational changes that induce Bax oligomerization, we determined crystal structures of BaxΔC21 treated with detergents and BH3 peptides. The peptides bound the Bax canonical surface groove but, unlike their complexes with prosurvival relatives, dissociated Bax into two domains. The structures define the sequence signature of activator BH3 domains and reveal how they can activate Bax via its groove by favoring release of its BH3 domain. Furthermore, Bax helices α2-α5 alone adopted a symmetric homodimer structure, supporting the proposal that two Bax molecules insert their BH3 domain into each other's surface groove to nucleate oligomerization. A planar lipophilic surface on this homodimer may engage the membrane. Our results thus define critical Bax transitions toward apoptosis.
Truncated Latrunculins as Actin Inhibitors Targeting Plasmodium falciparum Motility and Host Cell Invasion
Publisher: American Chemical Society (ACS)
Date: 02-12-2016
Structure-Guided Development of Potent Benzoylurea Inhibitors of BCL-XL and BCL-2
Publisher: American Chemical Society (ACS)
Date: 27-04-2021
The Effect of the FIFA 11 + with Added Neck Exercises on Maximal Isometric Neck Strength and Peak Head Impact Magnitude During Heading: A Pilot Study
Publisher: Springer Science and Business Media LLC
Date: 29-09-2021
Evolution of the thyroid hormone distributor protein transthyretin in microbes, C. elegans, and vertebrates
Publisher: Wiley
Date: 04-2005
Abstract: Transthyretin (TTR) is an extracellular thyroid hormone distributor protein in vertebrates, whose structure has been highly conserved between fish and humans. However, the ligand preferentially bound by TTR has changed during evolution from 3',3,5-L-triiodothyronine (T3) to 3',5',3,5-l-tetraiodothyronine (T4). We identified genes in the genomes of >50 species of nonvertebrates, which could code for TTR-like proteins. Molecular modeling suggested most would have similar 3D structures and electrostatic surface potentials to vertebrate TTRs. We lified TTR-like genes from a C. elegans cDNA library, demonstrating that it is transcribed. We synthesized recombinant TTR-like proteins from S. dublin and C. elegans. These proteins form tetramers similarly to vertebrate TTRs, but their ligands remain elusive.
Solvation effects on zwitterion formation
Publisher: American Chemical Society (ACS)
Date: 05-1998
DOI: 10.1021/JP980627S
Structural insights into the degradation of Mcl-1 induced by BH3 domains
Publisher: Proceedings of the National Academy of Sciences
Date: 10-04-2007
Abstract: Apoptosis is held in check by prosurvival proteins of the Bcl-2 family. The distantly related BH3-only proteins bind to and antagonize them, thereby promoting apoptosis. Whereas binding of the BH3-only protein Noxa to prosurvival Mcl-1 induces Mcl-1 degradation by the proteasome, binding of another BH3-only ligand, Bim, elevates Mcl-1 protein levels. We compared the three-dimensional structures of the complexes formed between BH3 peptides of both Bim and Noxa, and we show that a discrete C-terminal sequence of the Noxa BH3 is necessary to instigate Mcl-1 degradation.
Evaluating the validity and reliability of inertial measurement units for determining knee and trunk kinematics during athletic landing and cutting movements
Publisher: Elsevier BV
Date: 10-2021
Solution structure of an ultra-stable single-chain insulin analog connects protein dynamics to a novel mechanism of receptor binding
Publisher: Elsevier BV
Date: 2018
New Theoretical and Experimental Proton Affinities for Methyl Halides and Diazomethane: A Revision of the Methyl Cation Affinity Scale
Publisher: American Chemical Society (ACS)
Date: 12-1994
DOI: 10.1021/J100101A001
The Role of Virtual Screening in Computer Aided Structure-Based Drug Design
Publisher: CSIRO Publishing
Date: 2004
DOI: 10.1071/CH04161
Abstract: The pharmaceutical industry has embraced computational methods to improve the successful negotiation of hits and leads into drugs in the clinic. This review examines the current status of in silico screening methods and aspects of compound library design.
Improving data acquisition speed and accuracy in sport using neural networks
Publisher: Informa UK Limited
Date: 14-10-2021
Structural and Functional Diversities among μ-Conotoxins Targeting TTX-resistant Sodium Channels
Publisher: American Chemical Society (ACS)
Date: 24-02-2006
DOI: 10.1021/BI052162J
Abstract: mu-Conotoxins are peptides that block sodium channels. Molecular cloning was used to identify four novel mu-conotoxins: CnIIIA, CnIIIB, CIIIA, and MIIIA from Conus consors, C. catus and C. magus. A comparison of their sequences with those of previously characterized mu-conotoxins suggested that the new mu-conotoxins were likely to target tetrodotoxin-resistant (TTX-r) sodium channels. The four peptides were chemically synthesized, and their biological activities were characterized. The new conotoxins all blocked, albeit with varying potencies, TTX-r sodium currents in frog dorsal-root-ganglion (DRG) neurons. The more potent of the four new mu-conotoxins, CnIIIA and CIIIA, exhibited a strikingly different selectivity profile in blocking TTX-r versus TTX-sensitive channels, as determined by their ability to block extracellularly recorded action potentials in three preparations from frog: skeletal muscle, cardiac muscle and TTX-treated C-fibers. CnIIIA was highly specific for TTX-r sodium channels, whereas CIIIA was nonselective. Both peptides appeared significantly less potent in blocking TTX-r sodium currents in rat and mouse DRG neurons. When CnIIIA and CIIIA were injected intracranially into mice, both induced seizures, but only CIIIA caused paralysis. This is the most comprehensive characterization to date of the structural and functional ersities of an emerging group of mu-conotoxins targeting TTX-r sodium channels.
An aspartyl protease defines a novel pathway for export of Toxoplasma proteins into the host cell
Publisher: eLife Sciences Publications, Ltd
Date: 18-11-2015
DOI: 10.7554/ELIFE.10809
Abstract: Infection by Toxoplasma gondii leads to massive changes to the host cell. Here, we identify a novel host cell effector export pathway that requires the Golgi-resident aspartyl protease 5 (ASP5). We demonstrate that ASP5 cleaves a highly constrained amino acid motif that has similarity to the PEXEL-motif of Plasmodium parasites. We show that ASP5 matures substrates at both the N- and C-terminal ends of proteins and also controls trafficking of effectors without this motif. Furthermore, ASP5 controls establishment of the nanotubular network and is required for the efficient recruitment of host mitochondria to the vacuole. Assessment of host gene expression reveals that the ASP5-dependent pathway influences thousands of the transcriptional changes that Toxoplasma imparts on its host cell. All these changes result in attenuation of virulence of Δasp5 tachyzoites in vivo. This work characterizes the first identified machinery required for export of Toxoplasma effectors into the infected host cell.
Insights into Duffy Binding-like Domains through the Crystal Structure and Function of the Merozoite Surface Protein MSPDBL2 from Plasmodium falciparum
Publisher: Elsevier BV
Date: 09-2012
An evaluation of the performance of density functional theory, MP2, MP4, F4, G2(MP2) and G2 procedures in predicting gas-phase proton affinities
Publisher: Elsevier BV
Date: 12-1994
Quantitative in vivo Analyses Reveal Calcium-dependent Phosphorylation Sites and Identifies a Novel Component of the Toxoplasma Invasion Motor Complex
Publisher: Public Library of Science (PLoS)
Date: 29-09-2011
Active site modulation in the N-acetylneuraminate lyase sub-family as revealed by the structure of the inhibitor-complexed Haemophilus influenzae enzyme
Publisher: Elsevier BV
Date: 10-2000
Structure of a calcium-deficient form of influenza virus neuraminidase: implications for substrate binding
Publisher: International Union of Crystallography (IUCr)
Date: 19-08-2006
PS – a program for the analysis of helix geometry
Publisher: Elsevier BV
Date: 03-2012
DOI: 10.1016/J.JMGM.2011.11.004
Abstract: The structure of helices within proteins is often distorted from the ideal linear topology. Curvature of the helix axis can be measured by determining the radius of a circle fit to the axis. Described here is a method of defining a curved path that places backbone atoms (usually Cα) equidistantly from the path. The variance in the distance of backbone atoms from the helix axis is minimised to produce the parametric equations that describe the intersection of a sphere and a plane. The geometric properties of the helix (including helix radius, radius of curvature, and pitch) can be readily obtained from these equations. The approach is applicable to any form of helix, can use any atom in the peptide to determine the axis, can be applied to any polypeptide including mixed α/β peptides, and does not rely on a regular spacing of peptide monomers in the polypeptide chain.
Analysis of structure and function of the giant protein Pf332 in Plasmodium falciparum
Publisher: Wiley
Date: 29-12-2008
BCL-2 family protein BOK is a positive regulator of uridine metabolism in mammals
Publisher: Proceedings of the National Academy of Sciences
Date: 16-07-2019
Abstract: It is believed that the Bcl-2 family protein Bok has a redundant role similar to Bax and Bak in regulating apoptosis. We report that this protein interacts with the key enzyme involved in uridine biosynthesis, uridine monophosphate synthetase, and positively regulates uridine biosynthesis and chemoconversion of 5-fluorouracil (5-FU). Bok-deficient cell lines are resistant to 5-FU. Bok down-regulation is a key feature of cell lines and primary colorectal tumor tissues that are resistant to 5-FU. Our data also show that through its impact on nucleotide metabolism, Bok regulates p53 level and cellular proliferation. Our results have implications for developing Bok as a biomarker for 5-FU resistance and for the development of BOK mimetics for sensitizing 5-FU-resistant cancers.
Three-dimensional Structure of the Barley β-d-Glucan Glucohydrolase in Complex with a Transition State Mimic
Publisher: Elsevier BV
Date: 02-2004
Membrane Core-Specific Antimicrobial Action of Cathelicidin LL-37 Peptide Switches Between Pore and Nanofibre Formation
Publisher: Springer Science and Business Media LLC
Date: 30-11-2016
DOI: 10.1038/SREP38184
Abstract: Membrane-disrupting antimicrobial peptides provide broad-spectrum defence against localized bacterial invasion in a range of hosts including humans. The most generally held consensus is that targeting to pathogens is based on interactions with the head groups of membrane lipids. Here we show that the action of LL-37, a human antimicrobial peptide switches the mode of action based on the structure of the alkyl chains, and not the head groups of the membrane forming lipids. We demonstrate that LL-37 exhibits two distinct interaction pathways: pore formation in bilayers of unsaturated phospholipids and membrane modulation with saturated phospholipids. Uniquely, the membrane modulation yields helical-rich fibrous peptide-lipid superstructures. Our results point at alternative design strategies for peptide antimicrobials.
Theoretical and experimental structures of vinyl fluoride and vinyl alcohol
Publisher: AIP Publishing
Date: 11-1992
DOI: 10.1063/1.463721
Abstract: A new theoretical r0 structure for vinyl fluoride has been derived using ab initio molecular orbital procedures. In addition, new experimental r0 and rs structures have been obtained through a reanalysis of existing experimental microwave data. Significant discrepancies are found between the new theoretical (125.4°) and experimental (127.6°) r0 estimates of the CCHu angle involving the hydrogen atom geminal to the substituted center. This is attributed to the relative insensitivity of the experimental structural fits to the precise value of this bond angle, an insensitivity that is associated with the proximity of the relevant atoms to inertial axes. Because of these difficulties, the best estimate of the experimental r0 structure for vinyl fluoride is obtained by taking the theoretical r0 value for the CCHu angle and determining the remaining parameters by a weighted-least-squares fit to the experimental data. Weighted-least-squares fits are found generally to provide more consistency in the derived structural parameters than unweighted procedures. It is found that fitting of isotopic differences in rotational constants (as opposed to the conventional fitting of rotational constants themselves) provides the structure for vinyl fluoride most similar to the theoretical r0 structure. Similar observations are found to hold for vinyl alcohol, for which new theoretical and experimental results are presented.
Solution Structure of Ectodomains of the Insulin Receptor Family: The Ectodomain of the Type 1 Insulin-Like Growth Factor Receptor Displays Asymmetry of Ligand Binding Accompanied by Limited Conformat
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.JMB.2009.10.011
Abstract: The insulin receptor (IR) and the homologous Type 1 insulin-like growth factor receptor (IGF-1R) are cell-surface tyrosine kinase receptors that effect signaling within the respective pathways of glucose metabolism and normal human growth. While ligand binding to these receptors is assumed to result in a structural transition within the receptor ectodomain that then effects signal transduction across the cell membrane, little is known about the molecular detail of these events. Presented here are small-angle X-ray scattering data obtained from the IR and IGF-1R ectodomains in solution. We show that, in solution, the ectodomains of IR and IGF-1R have a domain disposition that is very similar to that seen in the crystal structure of the ectodomain of IR, despite the constituent domains being in relatively sparse contact and potentially mobile. We also show that the IGF-1R ectodomain is capable of binding up to three molecules of IGF-1 in solution, with surprisingly little apparent change in relative domain disposition compared to the apo form. While the observed 3:1 ligand-binding stoichiometry appears to contradict earlier explanations of the absence of a bell-shaped dose-response curve for IGF-1R in ligand displacement assays, it is readily understood in the context of the harmonic oscillator model of the negative cooperativity of ligand binding to IGF-1R. Taken together, our findings suggest that the structural movements within these receptors upon ligand binding are small and are possibly limited to local rotation of domains.
Insulin Mimetic Peptide Disrupts the Primary Binding Site of the Insulin Receptor
Publisher: Elsevier BV
Date: 07-2016
A Conformational Study of 2-Oxanol: Insight into the Role of Ring Distortion on Enzyme-Catalyzed Glycosidic Bond Cleavage
Publisher: American Chemical Society (ACS)
Date: 03-1997
DOI: 10.1021/JA9623020
Discovery, synthesis and exploration of N-benzylsulfonyl-2-phenylazepanes as inhibitors of Bim expression in a mouse embryonic fibroblast model
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.BIOORG.2022.105635
Abstract: Chronic activation of beta-adrenergic receptors by the sympathetic nervous system results in the apoptosis of cardiomyocytes. Due to the inability of cardiomyocytes to regenerate, this can result in heart failure. Upregulation of the pro-apoptotic protein Bim has been implicated as the cause of cardiomyocyte apoptosis. Beta blockers are the frontline drug used to negate this apoptotic pathway, as no direct inhibitors of Bim expression currently exist. Unfortunately, treatment of heart failure using beta blockers is not optimal. Therefore, direct inhibition of Bim expression is an attractive strategy to provide protection against stress-induced apoptosis of cardiomyocytes. Herein we explore a class of N-benzylsulfonyl-2-phenylazepanes to obtain anti-apoptotic compounds capable of reducing Bim expression levels to 7% of the control at 10 μM in cardiomyocytes under conditions of chronic beta-adrenergic receptor activation with little inhibitory effect upon protein kinase A activity and minimal toxicity.
Consequences of Two Different Amino-Acid Substitutions at the Same Codon in KRT14 Indicate Definitive Roles of Structural Distortion in Epidermolysis Bullosa Simplex Pathogenesis
Publisher: Elsevier BV
Date: 09-2011
DOI: 10.1038/JID.2011.143
Abstract: Numerous inherited diseases develop due to missense mutations, leading to an amino-acid substitution. Whether an amino-acid change is pathogenic depends on the level of deleterious effects caused by the amino-acid alteration. We show an ex le of different structural and phenotypic consequences caused by two in idual amino-acid changes at the same position. Epidermolysis bullosa simplex (EBS) is a genodermatosis resulting from KRT5 or KRT14 mutations. Mutation analysis of an EBS family revealed that affected in iduals were heterozygous for a, to our knowledge, previously unreported mutation of c.1237G>C (p.Ala413Pro) in KRT14. Interestingly, 2 of 100 unrelated normal controls were heterozygous, and 1 of the 100 was homozygous for a different mutation in this position, c.1237G>A (p.Ala413Thr). In silico modeling of the protein demonstrated deleterious structural effects from proline substitution but not from threonine substitution. In vitro transfection studies revealed a significantly larger number of keratin-clumped cells in HaCaT cells transfected with mutant KRT14 complementary DNA (cDNA) harboring p.Ala413Pro than those transfected with wild-type KRT14 cDNA or mutant KRT14 cDNA harboring p.Ala413Thr. These results show that changes in two distinct amino acids at a locus are destined to elicit different phenotypes due to the degree of structural distortion resulting from the amino-acid alterations.
A systematic review of propulsion from the flutter kick – What can we learn from the dolphin kick?
Publisher: Informa UK Limited
Date: 12-02-2018
DOI: 10.1080/02640414.2018.1436189
Abstract: Propulsion, one of the most important factors in front crawl swimming performance, is generated from both the upper and lower limbs, yet little is known about the mechanisms of propulsion from the alternating movements of the lower limbs in the flutter kick (FK). The purpose of this systematic review was to review the literature relating to the mechanisms of propulsion from FK in front crawl. There was limited information about the mechanisms of propulsion in FK. Since movements of the lower limbs are similar between FK and the dolphin kick (DK), mechanisms of propulsion from DK were reviewed to better understand propulsion from FK. Recent evidence suggests that propulsion in DK is generated in conjunction with formation and shedding of vortices. Similar vortex structures have been observed in FK. Visualisation and simulation techniques, such as particle image velocimetry (PIV) and computational fluid dynamics (CFD), are non-invasive tools that can effectively model water flow without impacting swimming technique. These technologies allow researchers to estimate the acceleration of water and, consequently, the propulsive reaction forces acting on the swimmer. Future research should use these technologies to investigate propulsion from FK.
A minimal sensor inertial measurement unit system is replicable and capable of estimating bilateral lower-limb kinematics in a stationary bodyweight squat and a countermovement jump
Publisher: Human Kinetics
Date: 02-2023
Abstract: This study aimed to validate a 7-sensor inertial measurement unit system against optical motion capture to estimate bilateral lower-limb kinematics. Hip, knee, and ankle sagittal plane peak angles and range of motion (ROM) were compared during bodyweight squats and countermovement jumps in 18 participants. In the bodyweight squats, left peak hip flexion (intraclass correlation coefficient [ICC] = .51), knee extension (ICC = .68) and ankle plantar flexion (ICC = .55), and hip (ICC = .63) and knee (ICC = .52) ROM had moderate agreement, and right knee ROM had good agreement (ICC = .77). Relatively higher agreement was observed in the countermovement jumps compared to the bodyweight squats, moderate to good agreement in right peak knee flexion (ICC = .73), and right (ICC = .75) and left (ICC = .83) knee ROM. Moderate agreement was observed for right ankle plantar flexion (ICC = .63) and ROM (ICC = .51). Moderate agreement (ICC .50) was observed in all variables in the left limb except hip extension, knee flexion, and dorsiflexion. In general, there was poor agreement for peak flexion angles, and at least moderate agreement for joint ROM. Future work will aim to optimize methodologies to increase usability and confidence in data interpretation by minimizing variance in system-based differences and may also benefit from expanding planes of movement.
BAK core dimers bind lipids and can be bridged by them
Publisher: Springer Science and Business Media LLC
Date: 14-09-2020
Theoretical and experimental structures of vinyl chloride and vinyl bromide
Publisher: AIP Publishing
Date: 03-1993
DOI: 10.1063/1.464022
Abstract: The structures of vinyl chloride and vinyl bromide have been determined by ab initio molecular orbital calculations, and corrections applied to obtain theoretical r0 values. The theoretical r0 structures agree very well with experimental r0 structures derived from recent microwave spectral data. This contrasts with the situation for vinyl alcohol and vinyl fluoride for which significant discrepancies have been found between theoretical and experimental estimates of the CCHu angles involving the hydrogen atom geminal to the substituted center. The present results reinforce our earlier conclusion that the theoretical values for this parameter for vinyl alcohol and vinyl fluoride are more reliable than the experimental values. Difficulties in the experimental structural determinations for vinyl fluoride and vinyl alcohol are attributed to the unusual insensitivity of the experimental moments of inertia to the values of the CCHu angles, resulting in turn from the close proximity to a principal inertial axis of two of the atoms that define the CCHu angles in these molecules. In contrast, all three atoms defining the CCHu angles in vinyl chloride and vinyl bromide are far removed from the inertial axes. As a consequence, the experimental moments of inertia are sensitively dependent on the value of the CCHu angle, and theoretical and experimental structures agree well. We conclude that suggestions that substituted ethenes present unusual difficulties for ab initio structural determinations are unfounded. Sensitivity curves are suggested as valuable indicators of potential problems in experimental structural determinations.
Kinematic Differences in Shoulder Roll and Hip Roll at Different Front Crawl Speeds in National Level Swimmers
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2020
DOI: 10.1519/JSC.0000000000003281
Abstract: Andersen, JT, Sinclair, PJ, McCabe, CB, and Sanders, RH. Kinematic differences in shoulder roll and hip roll at different front crawl speeds in National Level Swimmers. J Strength Cond Res 34(1): 20–25, 2020—Dry-land strength training is a common component of swimming programs however, its efficacy is contentious. A common criticism of dry-land strength training for swimming is a lack of specificity. An understanding of movement patterns in swimming can enable dry-land strength training programs to be developed to elicit adaptations that transfer to improvements in swimming performance. This study aimed to quantify the range and velocity of hip roll, shoulder roll, and torso twist (produced by differences in the relative angle between shoulder roll and hip roll) in front crawl at different swimming speeds. Longitudinal torso kinematics was compared between sprint and 400-m pace front crawl using 3D kinematics of 13 elite Scottish front crawl specialists. The range (sprint: 78.1° 400 m: 61.3°) and velocity of torso twist (sprint: 166.3°·s −1 400 m: 96.9°·s −1 ) were greater at sprint than 400-m pace. These differences were attributed to reductions in hip roll (sprint: 36.8° 400 m: 49.9°) without corresponding reductions in shoulder roll (sprint: 97.7° 400 m: 101.6°) when subjects swam faster. Shoulder roll velocity (sprint: 190.9°·s −1 400 m: 139.2°·s −1 ) and hip roll velocity (sprint: 75.5°·s −1 400 m: 69.1°·s −1 ) were greater at sprint than 400-m pace due to a higher stroke frequency at sprint pace (sprint: 0.95 strokes·s −1 400 m: 0.70 strokes·s −1 ). These findings imply that torques acting to rotate the upper torso and the lower torso are greater at sprint than 400-m pace. Dry-land strength training specificity can be improved by designing exercises that challenge the torso muscles to reproduce the torques required to generate the longitudinal kinematics in front crawl.
The Bak core dimer focuses triacylglycerides in the membrane
Publisher: Elsevier BV
Date: 02-2022
Hexalithiobenzene: beauty is in the eye of the beholder
Publisher: Elsevier BV
Date: 05-1993
Stabilizing the Pro-Apoptotic BimBH3 Helix (BimSAHB) Does Not Necessarily Enhance Affinity or Biological Activity
Publisher: American Chemical Society (ACS)
Date: 10-12-2012
DOI: 10.1021/CB3005403
Abstract: An attractive approach for developing therapeutic peptides is to enhance binding to their targets by stabilizing their α-helical conformation, for ex le, stabilized BimBH3 peptides (BimSAHB) designed to induce apoptosis. Unexpectedly, we found that such modified peptides have reduced affinity for their targets, the pro-survival Bcl-2 proteins. We attribute this loss in affinity to disruption of a network of stabilizing intramolecular interactions present in the bound state of the native peptide. Altering this network may compromise binding affinity, as in the case of the BimBH3 stapled peptide studied here. Moreover, cells exposed to these peptides do not readily undergo apoptosis, strongly indicating that BimSAHB is not inherently cell permeable.
Modulation of voltage-gated K + channels by the sodium channel β1 subunit
Publisher: Proceedings of the National Academy of Sciences
Date: 05-10-2012
Abstract: Voltage-gated sodium (Na V ) and potassium (K V ) channels are critical components of neuronal action potential generation and propagation. Here, we report that Na V β1 encoded by SCN1b , an integral subunit of Na V channels, coassembles with and modulates the biophysical properties of K V 1 and K V 7 channels, but not K V 3 channels, in an isoform-specific manner. Distinct domains of Na V β1 are involved in modulation of the different K V channels. Studies with channel chimeras demonstrate that Na V β1-mediated changes in activation kinetics and voltage dependence of activation require interaction of Na V β1 with the channel’s voltage-sensing domain, whereas changes in inactivation and deactivation require interaction with the channel’s pore domain. A molecular model based on docking studies shows Na V β1 lying in the crevice between the voltage-sensing and pore domains of K V channels, making significant contacts with the S1 and S5 segments. Cross-modulation of Na V and K V channels by Na V β1 may promote ersity and flexibility in the overall control of cellular excitability and signaling.
Rearrangement and dissociative reactions of the methanol radical cation (CH3OH.bul.+): a comparison of theory and experiment
Publisher: American Chemical Society (ACS)
Date: 10-1991
DOI: 10.1021/JA00021A013
Further Insights into the Effects of Pre-organizing the BimBH3 Helix
Publisher: American Chemical Society (ACS)
Date: 18-02-2014
DOI: 10.1021/CB400638P
High-level ab initio molecular orbital calculations of imine formation
Publisher: American Chemical Society (ACS)
Date: 29-05-1998
DOI: 10.1021/JP9810825
The Heat of Formation of Formaldimine
Publisher: CSIRO Publishing
Date: 1992
DOI: 10.1071/CH9920285
Abstract: Ab initio molecular orbital theory at the G 2 level has been used to predict new values for the heat of formation of formaldimine (CH2=NH): ?Hfº0 = 94 ±10 kJ mol-1 and ?Hfº298 = 86 ±10 kJ mol-1.
Structure and mechanism of a sub-family of enzymes related to N-acetylneuraminate lyase
Publisher: Elsevier BV
Date: 02-1997
Abstract: We describe here a sub-family of enzymes related both structurally and functionally to N-acetylneuraminate lyase. Two members of this family (N-acetylneuraminate lyase and dihydrodipicolinate synthase) have known three-dimensional structures and we now proceed to show their structural and functional relationship to two further proteins, trans-o-hydroxybenzylidenepyruvate hydratase-aldolase and D-4-deoxy-5-oxoglucarate dehydratase. These enzymes are all thought to involve intermediate Schiff-base formation with their respective substrates. In order to understand the nature of this intermediate, we have determined the three-dimensional structure of N-acetylneuraminate lyase in complex with hydroxypyruvate (a product analogue) and in complex with one of its products (pyruvate). From these structures we deduce the presence of a closely similar Schiff-base forming motif in all members of the N-acetylneuraminate lyase sub-family. A fifth protein, MosA, is also confirmed to be a member of the sub-family although the involvement of an intermediate Schiff-base in its proposed reaction is unclear.
A critical region in the mineralocorticoid receptor for aldosterone binding and activation by cortisol: Evidence for a common mechanism governing ligand binding specificity in steroid hormone receptors
Publisher: The Endocrine Society
Date: 04-2007
DOI: 10.1210/ME.2006-0246
Abstract: The amino acids that confer aldosterone binding specificity to the mineralocorticoid receptor (MR) remain to be determined. We had previously analyzed a panel of chimeras created between the MR and the glucocorticoid receptor and determined that amino acids 804–874 of the MR ligand binding domain are critical for aldosterone binding. In the present study a further series of chimeras was created within this region. The chimeras were analyzed by a transactivation assay and [3H]aldosterone binding, and the critical region was narrowed down to amino acids 820–844. Site-directed mutagenesis was used to create single and multiple amino acid substitutions in this region. These studies identified 12 of the 16 amino acids that differ in the MR and the glucocorticoid receptor in this region as being critical to conferring aldosterone responsivity. The amino acids that differ in the region 820–844 lie on the surface of the molecule and, therefore, it appears that MR ligand binding selectivity is conferred by residues that do not form part of the ligand binding pocket. Other studies have found that the corresponding regions of the androgen and glucocorticoid receptors are critical for the binding of natural and synthetic ligands, suggesting a common mechanism governing ligand binding specificity. The new chimeras also displayed, as previously reported, a dissociation between cortisol binding and transactivation and, intriguingly, only those that bound aldosterone with high affinity were activated by cortisol, suggesting a common mechanism that underlies specificity of aldosterone binding and the ability of cortisol to activate the MR.
Transition State Mimetics of the Plasmodium Export Element Are Potent Inhibitors of Plasmepsin V from P. falciparum and P. vivax
Publisher: American Chemical Society (ACS)
Date: 11-09-2014
DOI: 10.1021/JM500797G
Abstract: Following erythrocyte invasion, malaria parasites export a catalogue of remodeling proteins into the infected cell that enable parasite development in the human host. Export is dependent on the activity of the aspartyl protease, plasmepsin V (PMV), which cleaves proteins within the Plasmodium export element (PEXEL RxL↓xE/Q/D) in the parasite's endoplasmic reticulum. Here, we generated transition state mimetics of the native PEXEL substrate that potently inhibit PMV isolated from Plasmodium falciparum and Plasmodium vivax. Through optimization, we identified that the activity of the mimetics was completely dependent on the presence of P1 Leu and P3 Arg. Treatment of P. falciparum-infected erythrocytes with a set of optimized mimetics impaired PEXEL processing and killed the parasites. The striking effect of the compounds provides a clearer understanding of the accessibility of the PMV active site and reaffirms the enzyme as an attractive target for the design of future antimalarials.
Development of recombinant protein-based influenza vaccine
Publisher: Elsevier BV
Date: 12-2006
DOI: 10.1016/J.CHROMA.2006.09.067
Abstract: The influenza virus surface glycoprotein antigen neuraminidase (NA) is a crucial viral enzyme with many potential medical applications therefore, the development of efficient upstream and downstream processing strategy for the expression and purification of NA is of high importance. In the present work the NA gene from the H1N1 influenza virus strain A/Beijing/262/95 was cloned from viral RNA and expressed in expresSF+ insect cells using the baculovirus expression vector system (BVES). A limited affinity-ligand library was synthesized and evaluated for its ability to bind and purify the recombinant H1N1 neuraminidase. Affinity-ligand design was based on mimicking the interactions of the lock-and-key (LAK) motif (Phe-Gly-Gln), a common structural moiety found in the subunit interface of glutathione S-transferase I (GST I), and plays an important structural role in subunit-subunit recognition. Solid-phase combinatorial chemistry was used to synthesize 13 variants of the lock-and-key lead ligand (Phe-Trz-X, where X was selected alpha-amino acid) using the 1,3,5-triazine moiety (Trz) as the scaffold for assembly. One immobilized ligand, bearing phenylalanine and isoleucine linked on the chlorotriazine ring (Phe-Trz-Ile), displayed high affinity for NA. Absorption equilibrium and molecular modeling studies were carried out to provide a detailed picture of Phe-Trz-Ile interaction with NA. This LAK-mimetic affinity adsorbent was exploited in the development of a facile purification protocol for NA, which led to 335-fold purification in a single-step. The present purification procedure is the most efficient reported so far for recombinant NA.
Conformational preferences ofXONO2 systems (X = H, F, Cl, CH3) fromab initio techniques
Publisher: Wiley
Date: 06-1991
Analysis of Pushing Exercises
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2014
Structure-Guided Rational Design of α/β-Peptide Foldamers with High Affinity for BCL-2 Family Prosurvival Proteins
Publisher: Wiley
Date: 08-08-2013
Structural analysis of bioinspired nano materials with synchrotron far IR spectroscopy
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6CP01355D
Abstract: Synchrotron far-infrared spectroscopy was used in conjunction with density functional theory vibrational analysis to ascertain the core structure of self-assembled fibrous superstructures formed by unnatural β 3 -tripeptides.
Structure/Function Characterization of μ-Conotoxin KIIIA, an Analgesic, Nearly Irreversible Blocker of Mammalian Neuronal Sodium Channels
Publisher: Elsevier BV
Date: 10-2007
Calculation of aqueous dissociation constants of 1,2,4-triazole and tetrazole: A comparison of solvation models
Publisher: Royal Society of Chemistry (RSC)
Date: 2002
DOI: 10.1039/B203118C
Protective hinge in insulin opens to enable its receptor engagement
Publisher: Proceedings of the National Academy of Sciences
Date: 04-08-2014
Abstract: Insulin provides a model for analysis of protein structure and evolution. Here we describe in detail a conformational switch that enables otherwise hidden nonpolar surfaces in the hormone to engage its receptor. Whereas the classical closed conformation of insulin enables its stable storage in pancreatic β cells, its active conformation is open and susceptible to nonnative aggregation. Our findings illuminate biophysical constraints underlying the evolution of an essential signaling system and provide a structural foundation for design of therapeutic insulin analogs.
Structural resolution of a tandem hormone-binding element in the insulin receptor and its implications for design of peptide agonists
Publisher: Proceedings of the National Academy of Sciences
Date: 26-03-2010
Abstract: The C-terminal segment of the human insulin receptor α-chain (designated αCT) is critical to insulin binding as has been previously demonstrated by alanine scanning mutagenesis and photo-cross-linking. To date no information regarding the structure of this segment within the receptor has been available. We employ here the technique of thermal-factor sharpening to enhance the interpretability of the electron-density maps associated with the earlier crystal structure of the human insulin receptor ectodomain. The αCT segment is now resolved as being engaged with the central β-sheet of the first leucine-rich repeat (L1) domain of the receptor. The segment is α-helical in conformation and extends 11 residues N-terminal of the classical αCT segment boundary originally defined by peptide mapping. This tandem structural element (αCT-L1) thus defines the intact primary insulin-binding surface of the apo -receptor. The structure, together with isothermal titration calorimetry data of mutant αCT peptides binding to an insulin minireceptor, leads to the conclusion that putative “insulin-mimetic” peptides in the literature act at least in part as mimics of the αCT segment as well as of insulin. Photo-cross-linking by novel bifunctional insulin derivatives demonstrates that the interaction of insulin with the αCT segment and the L1 domain occurs in trans , i.e., these components of the primary binding site are contributed by alternate α-chains within the insulin receptor homodimer. The tandem structural element defines a new target for the design of insulin agonists for the treatment of diabetes mellitus.
Domain reorientation and rotation of an intracellular assembly regulate conduction in kir potassium channels
Publisher: Elsevier BV
Date: 06-2010
DOI: 10.1016/J.CELL.2010.05.003
Abstract: Potassium channels embedded in cell membranes employ gates to regulate K+ current. While a specific constriction in the permeation pathway has historically been implicated in gating, recent reports suggest that the signature ion selectivity filter located in the outer membrane leaflet may be equally important. Inwardly rectifying K+ channels also control the directionality of flow, using intracellular polyamines to stem ion efflux by a valve-like action. This study presents crystallographic evidence of interdependent gates in the conduction pathway and reveals the mechanism of polyamine block. Reorientation of the intracellular domains, concomitant with activation, instigates polyamine release from intracellular binding sites to block the permeation pathway. Conformational adjustments of the slide helices, achieved by rotation of the cytoplasmic assembly relative to the pore, are directly correlated to the ion configuration in the selectivity filter. Ion redistribution occurs irrespective of the constriction, suggesting a more expansive role of the selectivity filter in gating than previously appreciated.
A constricted opening in Kir channels does not impede potassium conduction
Publisher: Springer Science and Business Media LLC
Date: 15-06-2020
DOI: 10.1038/S41467-020-16842-0
Abstract: The canonical mechanistic model explaining potassium channel gating is of a conformational change that alternately dilates and constricts a collar-like intracellular entrance to the pore. It is based on the premise that K + ions maintain a complete hydration shell while passing between the transmembrane cavity and cytosol, which must be accommodated. To put the canonical model to the test, we locked the conformation of a Kir K + channel to prevent widening of the narrow collar. Unexpectedly, conduction was unimpaired in the locked channels. In parallel, we employed all-atom molecular dynamics to simulate K + ions moving along the conduction pathway between the lower cavity and cytosol. During simulations, the constriction did not significantly widen. Instead, transient loss of some water molecules facilitated K + permeation through the collar. The low free energy barrier to partial dehydration in the absence of conformational change indicates Kir channels are not gated by the canonical mechanism.
Fish-hunting cone snail venoms are a rich source of minimized ligands of the vertebrate insulin receptor
Publisher: eLife Sciences Publications, Ltd
Date: 12-02-2019
DOI: 10.7554/ELIFE.41574
Abstract: The fish-hunting marine cone snail Conus geographus uses a specialized venom insulin to induce hypoglycemic shock in its prey. We recently showed that this venom insulin, Con-Ins G1, has unique characteristics relevant to the design of new insulin therapeutics. Here, we show that fish-hunting cone snails provide a rich source of minimized ligands of the vertebrate insulin receptor. Insulins from C. geographus , Conus tulipa and Conus kinoshitai exhibit erse sequences, yet all bind to and activate the human insulin receptor. Molecular dynamics reveal unique modes of action that are distinct from any other insulins known in nature. When tested in zebrafish and mice, venom insulins significantly lower blood glucose in the streptozotocin-induced model of diabetes. Our findings suggest that cone snails have evolved erse strategies to activate the vertebrate insulin receptor and provide unique insight into the design of novel drugs for the treatment of diabetes.
Quinazoline sulfonamides as dual binders of the proteins B-cell lymphoma 2 and B-cell lymphoma extra long with potent proapoptotic cell-based activity.
Publisher: American Chemical Society (ACS)
Date: 02-03-2011
DOI: 10.1021/JM101596E
The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1β production
Publisher: Proceedings of the National Academy of Sciences
Date: 27-06-2006
Abstract: Familial Mediterranean fever (FMF) is a recessively inherited autoinflammatory disorder with high carrier frequencies in the Middle East. Pyrin, the protein mutated in FMF, regulates caspase-1 activation and consequently IL-1β production through cognate interaction of its N-terminal PYRIN motif with the ASC adaptor protein. However, the preponderance of mutations reside in pyrin’s C-terminal B30.2 domain. Here we demonstrate direct interaction of this domain with caspase-1. In lysates from cells not expressing ASC, reciprocal GST pull-downs demonstrated the interaction of pyrin with the p20 and p10 catalytic subunits of caspase-1. Coimmunoprecipitations of pyrin and caspase-1 from THP-1 human monocytic cells were consistent with the interaction of endogenous proteins. The C-terminal B30.2 domain of pyrin is necessary and sufficient for the interaction, and binding was reduced by FMF-associated B30.2 mutations. Full-length pyrin attenuated IL-1β production in cells transfected with a caspase-1/IL-1β construct, an effect diminished by FMF-associated B30.2 mutations and in B30.2 deletion mutants. Modeling of the crystal structure of caspase-1 with the deduced structure of the pyrin B30.2 domain corroborated both the interaction and the importance of M694V and M680I pyrin mutations. Consistent with a net inhibitory effect of pyrin on IL-1β activation, small interfering RNA (siRNA)-mediated pyrin knockdown in THP-1 cells augmented IL-1β production in response to bacterial LPS. Moreover, the IL-1 receptor antagonist anakinra suppressed acute-phase proteins in a patient with FMF and amyloidosis. Our data support a direct, ASC-independent effect of pyrin on IL-1β activation and suggest heightened IL-1 responsiveness as one factor selecting for pyrin mutations.
Differential Targeting of Prosurvival Bcl-2 Proteins by Their BH3-Only Ligands Allows Complementary Apoptotic Function
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1016/J.MOLCEL.2004.12.030
Abstract: Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1. Strikingly, Noxa bound only Mcl-1 and A1. In accord with their complementary binding, Bad and Noxa cooperated to induce potent killing. The results suggest that apoptosis relies on selective interactions between particular subsets of these proteins and that it should be feasible to discover BH3-mimetic drugs that inactivate specific prosurvival targets.
Determinants of spironolactone binding specificity in the mineralocorticoid receptor
Publisher: Bioscientifica
Date: 12-2003
Abstract: Spironolactone is a mineralocorticoid receptor (MR) antagonist in clinical use. The compound has a very low affinity for the glucocorticoid receptor (GR). Determinants of binding specificity of spironolactone to the MR were investigated using chimeras created between the ligand-binding domains (LBDs) of the MR and the GR. These chimeras had previously been used to investigate aldosterone binding specificity to the MR. Spironolactone was able to compete strongly for [(3)H]-aldosterone and [(3)H]-dexamethasone binding to a chimera containing amino acids 804-874 of the MR, and weakly for [(3)H]-dexamethasone binding to a chimera containing amino acids 672-803 of the MR. Amino acids 804-874 were also critical for aldosterone binding specificity. Models of the MR LBD bound to aldosterone and spironolactone were created based on the crystal structure of the progesterone receptor LBD. The ligand-binding pocket of the MR LBD model consisted of 23 amino acids and was predominantly hydrophobic in nature. Analysis of this model in light of the experimental data suggested that spironolactone binding specificity is not governed by amino acids in the ligand-binding pocket.
Intracellular Trafficking of the KV1.3 Potassium Channel Is Regulated by the Prodomain of a Matrix Metalloprotease
Publisher: Elsevier BV
Date: 03-2013
The relationship between general measures of fitness, passive range of motion and whole-body movement quality
Publisher: Informa UK Limited
Date: 04-2013
DOI: 10.1080/00140139.2011.620177
Abstract: The goal of this study was to establish relationships between fitness (torso endurance, grip strength and pull-ups), hip range of motion (ROM) (extension, flexion, internal and external rotation) and movement quality in an occupational group with physical work demands. Fifty-three men from the emergency task force of a major city police force were investigated. The movement screen comprised standing and seated posture, gait, segmental spine motion and 14 tasks designed to challenge whole-body coordination. Relationships were established between each whole-body movement task, the measures of strength, endurance and ROM. In general, fitness and ROM were not strongly related to the movement quality of any task. This has implications for worker training, in that strategies developed to improve ROM or strength about a joint may not enhance movement quality. Worker-centered injury prevention can be described as fitting workers to tasks by improving fitness and modifying movement patterns however, the current results show weak correlations between strength, endurance and ROM, and the way in iduals move. Therefore, the development of occupation-specific injury prevention strategies may require both fitness and movement-oriented objectives.
Properties of GDP-mannose Pyrophosphorylase, a Critical Enzyme and Drug Target in Leishmania mexicana
Publisher: Elsevier BV
Date: 03-2004
Predicting the Enthalpy and Gibbs Energy of Sublimation by QSPR Modeling
Publisher: Springer Science and Business Media LLC
Date: 27-06-2018
DOI: 10.1038/S41598-018-28105-6
Abstract: The enthalpy and Gibbs energy of sublimation are predicted using quantitative structure property relationship (QSPR) models. In this study, we compare several approaches previously reported in the literature for predicting the enthalpy of sublimation. These models, which were reproduced successfully, exhibit high correlation coefficients, in the range 0.82 to 0.97. There are significantly fewer ex les of QSPR models currently described in the literature that predict the Gibbs energy of sublimation here we describe several models that build upon the previous models for predicting the enthalpy of sublimation. The most robust and predictive model constructed using multiple linear regression, with the fewest number of descriptors for estimating this property, was obtained with an R 2 of the training set of 0.71, an R 2 of the test set of 0.62, and a standard deviation of 9.1 kJ mol −1 . This model could be improved by training using a neural network, yielding an R 2 of the training and test sets of 0.80 and 0.63, respectively, and a standard deviation of 8.9 kJ mol −1 .
The effect of N-methylation on transition state mimetic inhibitors of the Plasmodium protease, plasmepsin V
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4MD00409D
Abstract: An N -methylation strategy has been applied to transition state mimetics that are potent inhibitors of plasmepsin V to improve their physical characteristics and their ability to reduce the viability of Plasmodium parasites in culture.
From Cyclohexane to 2-Hydroxy-3-oxanone: A Conformation Study
Publisher: American Chemical Society (ACS)
Date: 05-1998
DOI: 10.1021/JP980037U
The effect of ball characteristics on head acceleration during purposeful heading in male and female youth football players.
Publisher: Informa UK Limited
Date: 07-04-2021
Gaussian-theory predictions of proton transfer to water of phenol and 3-chlorophenol: resolution of an apparent difficulty
Publisher: Elsevier BV
Date: 07-2001
Structure-guided design of a selective BCL-XL inhibitor
Publisher: Springer Science and Business Media LLC
Date: 21-04-2013
Cubylcarbinyl Cation: Fact or Fiction?
Publisher: American Chemical Society (ACS)
Date: 08-1997
DOI: 10.1021/JO970323M
Crystal structure of PfRh5, an essential P. falciparum ligand for invasion of human erythrocytes
Publisher: eLife Sciences Publications, Ltd
Date: 08-10-2014
DOI: 10.7554/ELIFE.04187
Abstract: Plasmodium falciparum causes the most severe form of malaria in humans and is responsible for over 700,000 deaths annually. It is an obligate intracellular parasite and invades erythrocytes where it grows in a relatively protected niche. Invasion of erythrocytes is essential for parasite survival and this involves interplay of multiple protein–protein interactions. One of the most important interactions is binding of parasite invasion ligand families EBLs and PfRhs to host receptors on the surface of erythrocytes. PfRh5 is the only essential invasion ligand within the PfRh family and is an important vaccine candidate. PfRh5 binds the host receptor basigin. In this study, we have determined the crystal structure of PfRh5 using diffraction data to 2.18 Å resolution. PfRh5 exhibits a novel fold, comprising nine mostly anti-parallel α-helices encasing an N-terminal β-hairpin, with the overall shape being an elliptical disk. This is the first three-dimensional structure determined for the PfRh family of proteins.
The ammonia dimer potential energy surface: resolution of the apparent discrepancy between theory and experiment?
Publisher: Elsevier BV
Date: 09-1991
Structure of Leishmania mexicana Phosphomannomutase Highlights Similarities with Human Isoforms
Publisher: Elsevier BV
Date: 10-2006
DOI: 10.1016/J.JMB.2006.08.023
Abstract: Phosphomannomutase (PMM) catalyses the conversion of mannose-6-phosphate to mannose-1-phosphate, an essential step in mannose activation and the biosynthesis of glycoconjugates in all eukaryotes. Deletion of PMM from Leishmania mexicana results in loss of virulence, suggesting that PMM is a promising drug target for the development of anti-leishmanial inhibitors. We report the crystallization and structure determination to 2.1 A of L. mexicana PMM alone and in complex with glucose-1,6-bisphosphate to 2.9 A. PMM is a member of the haloacid dehalogenase (HAD) family, but has a novel dimeric structure and a distinct cap domain of unique topology. Although the structure is novel within the HAD family, the leishmanial enzyme shows a high degree of similarity with its human isoforms. We have generated L. major PMM knockouts, which are avirulent. We expressed the human pmm2 gene in the Leishmania PMM knockout, but despite the similarity between Leishmania and human PMM, expression of the human gene did not restore virulence. Similarities in the structure of the parasite enzyme and its human isoforms suggest that the development of parasite-selective inhibitors will not be an easy task.
Polymorphisms in Erythrocyte Binding Antigens 140 and 181 Affect Function and Binding but Not Receptor Specificity in Plasmodium falciparum
Publisher: American Society for Microbiology
Date: 04-2009
DOI: 10.1128/IAI.01331-08
Abstract: Invasion of human erythrocytes by the malaria parasite Plasmodium falciparum utilizes multiple ligand-receptor interactions involving erythrocyte receptors and parasite erythrocyte binding proteins of the Duffy binding-like family. Erythrocyte binding antigen 175 (EBA-175) binds to glycophorin A, the most abundant protein on the human erythrocyte surface and EBA-140 (also known as BAEBL) binds to glycophorin C, while the receptor for EBA-181 (also known as JESEBL) remains unknown. EBA binding is mediated via region II, a highly structured extracellular domain that shows a degree of sequence variability between different laboratory strains/isolates. Here, we determined the influence of region II polymorphisms on host cell receptor binding and overall function during invasion of EBA-140, EBA-175, and EBA-181. Polymorphisms in the binding domains of EBA-140 and EBA-181 have been suggested previously to alter their respective receptor specificities. In our hands, these polymorphisms affected the levels of EBA-140 and EBA-181 binding to receptors but, critically, not the receptor specificities of these proteins. The degree of EBA-140 binding to glycophorin C correlates with the level of function for this ligand-receptor interaction in merozoite invasion. In contrast, EBA-175, which is highly polymorphic in region II, shows no variability in its ability to bind to its receptor, glycophorin A. Combined, these data highlight the importance of sequence variability in EBAs as driven by immune selection but not by receptor specificity.
Spiroleucettadine: synthetic studies and investigations towards structural revision
Publisher: Elsevier BV
Date: 03-2007
Characterization of the Two Fundamental Conformations of Benzoylureas and Elucidation of the Factors That Facilitate Their Conformational Interchange
Publisher: American Chemical Society (ACS)
Date: 07-08-2009
DOI: 10.1021/JO900871A
Abstract: The ability of the benzoylurea core to mimic alpha helices relies on its ability to form an intramolecular hydrogen bond. The conformational behavior of benzoylureas is investigated in depth in this study via the use of NMR, IR, X-ray, and computational analysis. The results show that the closed conformation maintained by an intramolecular hydrogen bond is favored in most of the cases studied except when steric and electronic effects combined with a solvent possessing a high hydrogen bond accepting ability, such as DMSO, are involved. The study highlights the propensity for benzoylureas to switch conformation depending on the environment of the molecule for a particular set of substituents. We anticipate that our summary of the phenomenon of internal hydrogen bonding and its analysis may further serve as a useful reference source for future workers in this area.
Muscle activity and spine load during anterior chain whole body linkage exercises: the body saw, hanging leg raise and walkout from a push-up
Publisher: Informa UK Limited
Date: 11-08-2014
DOI: 10.1080/02640414.2014.946437
Abstract: This study examined anterior chain whole body linkage exercises, namely the body saw, hanging leg raise and walkout from a push-up. Investigation of these exercises focused on which particular muscles were challenged and the magnitude of the resulting spine load. Fourteen males performed the exercises while muscle activity, external force and 3D body segment motion were recorded. A sophisticated and anatomically detailed 3D model used muscle activity and body segment kinematics to estimate muscle force, and thus sensitivity to each in idual's choice of motor control for each task. Gradations of muscle activity and spine load characteristics were observed across tasks. On average, the hanging straight leg raise created approximately 3000 N of spine compression while the body saw created less than 2500 N. The hanging straight leg raise created the highest challenge to the abdominal wall (>130% MVC in rectus abdominis, 88% MVC in external oblique). The body saw resulted in almost 140% MVC activation of the serratus anterior. All other exercises produced substantial abdominal challenge, although the body saw did so in the most spine conserving way. These findings, along with consideration of an in idual's injury history, training goals and current fitness level, should assist in exercise choice and programme design.
A Malaria Parasite Formin Regulates Actin Polymerization and Localizes to the Parasite-Erythrocyte Moving Junction during Invasion
Publisher: Elsevier BV
Date: 03-2008
DOI: 10.1016/J.CHOM.2008.02.006
Abstract: Malaria parasites invade host cells using actin-based motility, a process requiring parasite actin filament nucleation and polymerization. Malaria and other apicomplexan parasites lack Arp2/3 complex, an actin nucleator widely conserved across eukaryotes, but do express formins, another type of actin nucleator. Here, we demonstrate that one of two malaria parasite formins, Plasmodium falciparum formin 1 (PfFormin 1), and its ortholog in the related parasite Toxoplasma gondii, follows the moving tight junction between the invading parasite and the host cell, which is the predicted site of the actomyosin motor that powers motility. Furthermore, in vitro, the PfFormin1 actin-binding formin homology 2 domain is a potent nucleator, stimulating actin polymerization and, like other formins, localizing to the barbed end during filament elongation. These findings support a conserved molecular mechanism underlying apicomplexan parasite motility and, given the essential role that actin plays in cell invasion, highlight formins as important determinants of malaria parasite pathogenicity.
Diversity in the intrinsic apoptosis pathway of nematodes
Publisher: Springer Science and Business Media LLC
Date: 28-08-2020
DOI: 10.1038/S42003-020-01208-5
Abstract: Early studies of the free-living nematode C. elegans informed us how BCL-2-regulated apoptosis in humans is regulated. However, subsequent studies showed C. elegans apoptosis has several unique features compared with human apoptosis. To date, there has been no detailed analysis of apoptosis regulators in nematodes other than C. elegans . Here, we discovered BCL-2 orthologues in 89 free-living and parasitic nematode taxa representing four evolutionary clades (I, III, IV and V). Unlike in C. elegans , 15 species possess multiple (two to five) BCL-2-like proteins, and some do not have any recognisable BCL-2 sequences. Functional studies provided no evidence that BAX/BAK proteins have evolved in nematodes, and structural studies of a BCL-2 protein from the basal clade I revealed it lacks a functionally important feature of the C. elegans orthologue. Clade I CED-4/APAF-1 proteins also possess WD40-repeat sequences associated with apoptosome assembly, not present in C. elegans , or other nematode taxa studied.
Author Correction: A structurally minimized yet fully active insulin based on cone-snail venom insulin principles
Publisher: Springer Science and Business Media LLC
Date: 12-06-2020
Crystal structure and immunological properties of the first annexin from Schistosoma mansoni: Insights into the structural integrity of the schistosomal tegument
Publisher: Wiley
Date: 15-01-2014
DOI: 10.1111/FEBS.12700
Abstract: Schistosomiasis is a major parasitic disease of humans, second only to malaria in its global impact. The disease is caused by digenean trematodes that infest the vasculature of their human hosts. These flukes are limited externally by a body wall composed of a syncytial epithelium, the apical surface membrane of which is a parasitism-adapted dual membrane complex. Annexins are thought to be of integral importance for the stability of this apical membrane system. Here, we present the first structural and immunobiochemical characterization of an annexin from Schistosoma mansoni. The crystal structure of annexin B22 confirms the presence of the previously predicted α-helical segment in the II/III linker and reveals a covalently linked head-to-head dimer. From the calcium-bound crystal structure of this protein, canonical type II, type III and B site positions are occupied, and a novel binding site has been identified. The dimer arrangement observed in the crystal structure suggests the presence of two prominent features, a potential non-canonical membrane binding site and a potential binding groove opposite to the former. Results from transcriptional profiling during development show that annexin B22 expression is correlated with life stages of the parasite that possess the syncytial tegument layer, and ultrastructural localization by immuno-electron microscopy confirms the occurrence of annexins in the tegument of S. mansoni. Data from membrane binding and aggregation assays indicate the presence of differential molecular mechanisms and support the hypothesis of annexin B22 providing structural integrity in the tegument.
Effect of Ring Distortion on the Acid Hydrolysis of 2-Methylsulfanyloxane
Publisher: American Chemical Society (ACS)
Date: 19-05-1998
DOI: 10.1021/JP981096A
Structural insights into BCL2 pro-survival protein interactions with the key autophagy regulator BECN1 following phosphorylation by STK4/MST1
Publisher: Informa UK Limited
Date: 09-01-2019
Leishmania major CorA-like magnesium transporters play a critical role in parasite development and virulence
Publisher: Elsevier BV
Date: 05-2009
DOI: 10.1016/J.IJPARA.2008.11.010
Abstract: Establishment of infection by Leishmania depends on the transformation of the invading metacyclic promastigotes into the obligatory intracellular amastigotes, and their subsequent survival in the macrophage phagolysosome, which is low in magnesium. We show that two Leishmania major proteins designated MGT1 and MGT2, which play a critical role in these processes, belong to the two-transmembrane domain (2-TM-GxN) cation transporter family and share homology with the major bacterial magnesium transporter CorA. Although both are present in the endoplasmic reticulum throughout the life cycle of the parasite, MGT1 is more highly expressed in the infectious metacyclic parasites, while MGT2 is enriched in the immature procyclic stages. The two proteins, although predicted to be structurally similar, have features that suggest different regulatory or gating mechanisms. The two proteins may also be functionally distinct, since only MGT1 complements an Escherichia coli DeltaCorA mutant. In addition, deletion of one mgt1 allele from L. major led to increased virulence, while deletion of one allele of mgt2 resulted in slower growth and total loss of virulence in vitro and in vivo. This loss of virulence may be due to an impaired transformation of the parasites into amastigotes. Deletion of both mgt1 alleles in the hemizygous MGT2 knockdown parasites reversed the growth defect and partially restored virulence. Our data indicate that the MGTs play a critical role in parasite growth, development and virulence.
Structure of the Plasmodium falciparum PfSERA5 pseudo-zymogen
Publisher: Wiley
Date: 05-10-2020
DOI: 10.1002/PRO.3956
Structure of vinyl alcohol: a resolution of the discrepancy between theory and experiment
Publisher: American Chemical Society (ACS)
Date: 10-1990
DOI: 10.1021/JA00177A011
The energy difference between formaldehyde and hydroxymethylene radical cations: failure of unrestricted (UMP2) and restricted (RMP2) Møller—Plesset procedures
Publisher: Elsevier BV
Date: 06-1992
Gaussian-2 (G2) theory: Reduced basis set requirements
Publisher: AIP Publishing
Date: 04-1996
DOI: 10.1063/1.471141
Abstract: Two variations of G2(MP2) theory which employ smaller basis sets in evaluating the quadratic configuration interaction [QCISD(T)] component of the energy are presented. The first, G2(MP2,SVP), uses the split-valence plus polarization (SVP) 6-31G(d) basis, while the second, G2(MP2,SV), uses the split-valence (SV) 6-31G basis. The methods are evaluated on the basis of results for the set of 125 systems used for testing G2 theory. The mean absolute deviation of G2(MP2,SVP) results from experimental values is 1.63 kcal mol−1 compared with 1.58 and 1.21 kcal mol−1 for G2(MP2) and G2, respectively. The G2(MP2,SVP) method thus provides results which are generally very similar in quality to those obtained from G2(MP2) but at considerably reduced computational expense. On the other hand, the mean absolute deviation of G2(MP2,SV) results from experiment is substantially larger (2.13 kcal mol−1). The G2(MP2,SV) method exceeds the 2 kcal mol−1 target accuracy of G2 theory for an unacceptably large number of comparisons.
A markerless motion capture system can reliably determine peak trunk flexion while squatting with and without a weighted vest
Publisher: Elsevier BV
Date: 05-2023
Conotoxins Containing Nonnatural Backbone Spacers: Cladistic-Based Design, Chemical Synthesis, and Improved Analgesic Activity
Publisher: Elsevier BV
Date: 04-2007
DOI: 10.1016/J.CHEMBIOL.2007.02.009
Abstract: Disulfide-rich neurotoxins from venomous animals continue to provide compounds with therapeutic potential. Minimizing neurotoxins often results in removal of disulfide bridges or critical amino acids. To address this drug-design challenge, we explored the concept of disulfide-rich scaffolds consisting of isostere polymers and peptidic pharmacophores. Flexible spacers, such as amino-3-oxapentanoic or 6-aminohexanoic acids, were used to replace conformationally constrained parts of a three-disulfide-bridged conotoxin, SIIIA. The peptide-polymer hybrids, polytides, were designed based on cladistic identification of nonconserved loci in related peptides. After oxidative folding, the polytides appeared to be better inhibitors of sodium currents in dorsal root ganglia and sciatic nerves in mice. Moreover, the polytides appeared to be significantly more potent and longer-lasting analgesics in the inflammatory pain model in mice, when compared to SIIIA. The resulting polytides provide a promising strategy for transforming disulfide-rich peptides into therapeutics.
Optimization of Benzothiazole and Thiazole Hydrazones as Inhibitors of Schistosome BCL-2
Publisher: American Chemical Society (ACS)
Date: 02-2021
AB initio force constants: a cautionary tale concerning nitrogen oxides
Publisher: Elsevier BV
Date: 05-1989
The heat of formation of the acetyl cation: a theoretical evaluation
Publisher: Elsevier BV
Date: 12-1990
Muscle activity and spine load during pulling exercises: Influence of stable and labile contact surfaces and technique coaching
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.JELEKIN.2014.06.002
Abstract: This study examined pulling exercises performed on stable surfaces and unstable suspension straps. Specific questions included: which exercises challenged particular muscles, what was the magnitude of resulting spine load, and did technique coaching influence results. Fourteen males performed pulling tasks while muscle activity, external force, and 3D body segment motion were recorded. These data were processed and input to a sophisticated and anatomically detailed 3D model that used muscle activity and body segment kinematics to estimate muscle force, in this way the model was sensitive to each in idual's choice of motor control for each task. Muscle forces and linked segment joint loads were used to calculate spine loads. There were gradations of muscle activity and spine load characteristics to every task. It appears that suspension straps alter muscle activity less in pulling exercises, compared to studies reporting on pushing exercises. The chin-up and pull-up exercises created the highest spine load as they required the highest muscle activation, despite the body "hanging" under tractioning gravitational load. Coaching shoulder centration through retraction increased spine loading but undoubtedly adds proximal stiffness. An exercise atlas of spine compression was constructed to help with the decision making process of exercise choice for an in idual.
Crystal structure of ABT-737 complexed with Bcl-xL: implications for selectivity of antagonists of the Bcl-2 family.
Publisher: Springer Science and Business Media LLC
Date: 15-06-2007
The Trypanosomal Trans-Sialidase
Publisher: Elsevier BV
Date: 11-2002
DOI: 10.1016/S0969-2126(02)00888-2
Abstract: The structure of the trypanosomal trans-sialidase reveals a canonical sialidase catalytic site elaborated with a conformational switch that creates an adjacent binding pocket for lactose.
Extending Halogen-based Medicinal Chemistry to Proteins
Publisher: Elsevier BV
Date: 12-2016
Insight into the self-association of key enzymes from pathogenic species
Publisher: Springer Science and Business Media LLC
Date: 25-06-2005
DOI: 10.1007/S00249-005-0491-Y
Abstract: Self-association of protein monomers to higher-order oligomers plays an important role in a plethora of biological phenomena. The classical biophysical technique of analytical ultracentrifugation is a key method used to measure protein oligomerisation. Recent advances in sedimentation data analysis have enabled the effects of diffusion to be deconvoluted from s le heterogeneity, permitting the direct identification of oligomeric species in self-associating systems. Two such systems are described and reviewed in this study. First, we examine the enzyme dihydrodipicolinate synthase (DHDPS), which crystallises as a tetramer. Wild-type DHDPS plays a critical role in lysine biosynthesis in microbes and is therefore an important antibiotic target. To confirm the state of association of DHDPS in solution, we employed sedimentation velocity and sedimentation equilibrium studies in an analytical ultracentrifuge to show that DHDPS exists in a slow dimer-tetramer equilibrium with a dissociation constant of 76 nM. Second, we review works describing the hexamerisation of GDP-mannose pyrophosphorylase (GDP-MP), an enzyme that plays a critical role in mannose metabolism in Leishmania species. Although the structure of the GDP-MP hexamer has not yet been determined, we describe a three-dimensional model of the hexamer based largely on homology with the uridyltransferase enzyme, Glmu. GDP-MP is a novel drug target for the treatment of leishmaniasis, a devastating parasitic disease that infects more than 12 million people worldwide. Given that both GDP-MP and DHDPS are only active in their oligomeric states, we propose that inhibition of the self-association of critical enzymes in disease is an emerging paradigm for therapeutic intervention.
Evaluation of diverse α/β-backbone patterns for functional α-helix mimicry: Analogues of the Bim BH3 domain
Publisher: American Chemical Society (ACS)
Date: 08-12-2012
DOI: 10.1021/JA207148M
Identification of an activation site in Bak and mitochondrial Bax triggered by antibodies
Publisher: Springer Science and Business Media LLC
Date: 24-05-2016
DOI: 10.1038/NCOMMS11734
Abstract: During apoptosis, Bak and Bax are activated by BH3-only proteins binding to the α2–α5 hydrophobic groove Bax is also activated via a rear pocket. Here we report that antibodies can directly activate Bak and mitochondrial Bax by binding to the α1–α2 loop. A monoclonal antibody (clone 7D10) binds close to α1 in non-activated Bak to induce conformational change, oligomerization, and cytochrome c release. Anti-FLAG antibodies also activate Bak containing a FLAG epitope close to α1. An antibody (clone 3C10) to the Bax α1–α2 loop activates mitochondrial Bax, but blocks translocation of cytosolic Bax. Tethers within Bak show that 7D10 binding directly extricates α1 a structural model of the 7D10 Fab bound to Bak reveals the formation of a cavity under α1. Our identification of the α1–α2 loop as an activation site in Bak paves the way to develop intrabodies or small molecules that directly and selectively regulate these proteins.
Exercises to Activate the Deeper Abdominal Wall Muscles
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2014
Transferrin receptor 1 is a reticulocyte-specific receptor for Plasmodium vivax
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-01-2018
Abstract: Human malaria is caused by half a dozen species of Plasmodium protozoan parasites, each with distinctive biology. P. vivax , which causes relapsing malaria, specifically parasitizes immature red blood cells called reticulocytes. Gruszczyk et al. identified TfR1 (host transferrin receptor 1) as an alternative receptor for P. vivax . TfR1 binds to a specific P. vivax surface protein. However, the parasite that causes cerebral malaria, P. falciparum , does not share TfR1 as a receptor: P. falciparum could still infect cells in which TfR1 expression was knocked down, but P. vivax could not. Monoclonal antibodies to the P. vivax protein successfully hindered P. vivax infection of red blood cells. Science , this issue p. 48
Heat of formation for the hydroxymethylene radical cation: the importance of reverse activation energy
Publisher: American Chemical Society (ACS)
Date: 11-1989
DOI: 10.1021/J100360A007
An ab initio study of many isomers of S2O2. A combined theoretical and experimental analysis of the harmonic force field and molecular structure of cis-planar OSSO
Publisher: Elsevier BV
Date: 03-1990
Two essential light chains regulate the MyoA lever arm to promote toxoplasma gliding motility
Publisher: American Society for Microbiology
Date: 30-10-2015
Abstract: Key to the virulence of apicomplexan parasites is their ability to move through tissue and to invade and egress from host cells. Apicomplexan motility requires the activity of the glideosome, a multicomponent molecular motor composed of a type XIV myosin, MyoA. Here we identify a novel glideosome component, essential light chain 2 (ELC2), and functionally characterize the two essential light chains (ELC1 and ELC2) of MyoA in Toxoplasma . We show that these proteins are functionally redundant but are important for invasion, egress, and motility. Molecular simulations of the MyoA lever arm identify a role for Ca 2+ in promoting intermolecular contacts between the ELCs and the adjacent MLC1 light chain to stabilize this domain. Using point mutations predicted to ablate either the interaction with Ca 2+ or the interface between the two light chains, we demonstrate their contribution to the quality, displacement, and speed of gliding Toxoplasma parasites. Our work therefore delineates the importance of the MyoA lever arm and highlights a mechanism by which this domain could be stabilized in order to promote invasion, egress, and gliding motility in apicomplexan parasites. IMPORTANCE Tissue dissemination and host cell invasion by apicomplexan parasites such as Toxoplasma are pivotal to their pathogenesis. Central to these processes is gliding motility, which is driven by an actomyosin motor, the MyoA glideosome. Others have demonstrated the importance of the MyoA glideosome for parasite motility and virulence in mice. Disruption of its function may therefore have therapeutic potential, and yet a deeper mechanistic understanding of how it works is required. Ca 2+ -dependent and -independent phosphorylation and the direct binding of Ca 2+ to the essential light chain have been implicated in the regulation of MyoA activity. Here we identify a second essential light chain of MyoA and demonstrate the importance of both to Toxoplasma motility. We also investigate the role of Ca 2+ and the MyoA regulatory site in parasite motility and identify a potential mechanism whereby binding of a alent cation to the essential light chains could stabilize the myosin to allow productive movement.
Unimolecular rearrangements connecting hydroxyethylidene (CH3-C-OH), acetaldehyde (CH3-CH:O), and vinyl alcohol (CH2:CH-OH)
Publisher: American Chemical Society (ACS)
Date: 08-1991
DOI: 10.1021/JA00017A015
High-resolution structural characterization of a helical alpha/beta-peptide foldamer bound to the anti-apoptotic protein Bcl-xL.
Publisher: Wiley
Date: 02-06-2009
Catalytic mechanism and cofactor preference of dihydrodipicolinate reductase from methicillin-resistant Staphylococcus aureus
Publisher: Elsevier BV
Date: 08-2011
DOI: 10.1016/J.ABB.2011.06.006
Abstract: Given the rapid rise in antibiotic resistance, including methicillin resistance in Staphylococcus aureus (MRSA), there is an urgent need to characterize novel drug targets. Enzymes of the lysine biosynthesis pathway in bacteria are ex les of such targets, including dihydrodipicolinate reductase (DHDPR, E.C. 1.3.1.26), which is the product of an essential bacterial gene. DHDPR catalyzes the NAD(P)H-dependent reduction of dihydrodipicolinate (DHDP) to tetrahydrodipicolinate (THDP) in the lysine biosynthesis pathway. We show that MRSA-DHDPR exhibits a unique nucleotide specificity utilizing NADPH (K(m)=12μM) as a cofactor more effectively than NADH (K(m)=26μM). However, the enzyme is inhibited by high concentrations of DHDP when using NADPH as a cofactor, but not with NADH. Isothermal titration calorimetry (ITC) studies reveal that MRSA-DHDPR has ∼20-fold greater binding affinity for NADPH (K(d)=1.5μM) relative to NADH (K(d)=29μM). Kinetic investigations in tandem with ITC studies show that the enzyme follows a compulsory-order ternary complex mechanism with inhibition by DHDP through the formation of a nonproductive ternary complex with NADP(+). This work describes, for the first time, the catalytic mechanism and cofactor preference of MRSA-DHDPR, and provides insight into rational approaches to inhibiting this valid antimicrobial target.
The effect of ball characteristics on head impact magnitude during purposeful heading in adolescent male and female football players
Publisher: Elsevier BV
Date: 11-2021
Structural Rationale for Low-Nanomolar Binding of Transition State Mimics to a Family GH3 β-d -Glucan Glucohydrolase from Barley,
Publisher: American Chemical Society (ACS)
Date: 18-11-2005
DOI: 10.1021/BI0514818
Abstract: The interactions of a transition state mimic anilinomethyl glucoimidazole (AmGlcIm), with a K(i) constant of 0.6 x 10(-)(9) M and a Gibbs free energy value of -53.5 kJ/mol, with a family GH3 beta-d-glucan glucohydrolase from barley have been analyzed crystallographically and by ab initio quantum mechanical modeling. AmGlcIm binds 3 times more tightly to the beta-d-glucan glucohydrolase than a previously investigated phenyl glucoimidazole. In the enzyme-AmGlcIm complex, an additional residue, Tyr253, and a water molecule positioned between subsites -1 and +1 are recruited for binding. Analyses of the two binary complexes reveal the following. (i) An intricate network exists in which hydrogen bonds between the enzyme's catalytic pocket residues Lys206, His207, Tyr253, Asp285, and Glu491 and the glucoimidazoles are shorter by 0.15-0.53 A, compared with distances of hydrogen bonds in the Michaelis complex. (ii) The "glucose" moiety of the glucoimidazoles adopts a (4)E conformation that is vital for the low-nanomolar binding. (iii) The N1 atoms of the glucoimidazoles are positioned nearly optimally for in-line protonation by the Oepsilon1 atom of the catalytic acid/base Glu491. (iv) The enzyme derives binding energies from both glycone and aglycone components of the glucoimidazoles. (iv) The prevalent libration motion of the two domains of the enzyme could play a significant role during induced fit closure in the active site. (v) Modeling based on the structural data predicts that protons could be positioned on the N1 atoms of the glucoimidazoles, and the catalytic acid/base Glu491 could carry an overall negative charge. (vi) The enzyme-AmGlcIm complex reveals the likely structure of an early transition state during hydrolysis. Finally, the high-resolution structures enabled us to define minimal structures of oligosaccharides attached to Asn221, Asn498, and Asn600 N-glycosylation sites.
Domain structure and function of matrix metalloprotease 23 (MMP23): role in potassium channel trafficking
Publisher: Springer Science and Business Media LLC
Date: 03-08-2013
DOI: 10.1007/S00018-013-1431-0
Abstract: MMP23 is a member of the matrix metalloprotease family of zinc- and calcium-dependent endopeptidases, which are involved in a wide variety of cellular functions. Its catalytic domain displays a high degree of structural homology with those of other metalloproteases, but its atypical domain architecture suggests that it may possess unique functional properties. The N-terminal MMP23 pro-domain contains a type-II transmembrane domain that anchors the protein to the plasma membrane and lacks the cysteine-switch motif that is required to maintain other MMPs in a latent state during passage to the cell surface. Instead of the C-terminal hemopexin domain common to other MMPs, MMP23 contains a small toxin-like domain (TxD) and an immunoglobulin-like cell adhesion molecule (IgCAM) domain. The MMP23 pro-domain can trap Kv1.3 but not closely-related Kv1.2 channels in the endoplasmic reticulum, preventing their passage to the cell surface, while the TxD can bind to the channel pore and block the passage of potassium ions. The MMP23 C-terminal IgCAM domain displays some similarity to Ig-like C2-type domains found in IgCAMs of the immunoglobulin superfamily, which are known to mediate protein-protein and protein-lipid interactions. MMP23 and Kv1.3 are co-expressed in a variety of tissues and together are implicated in diseases including cancer and inflammatory disorders. Further studies are required to elucidate the mechanism of action of this unique member of the MMP family.
Calculation of aqueous proton dissociation constants of quinoline and hydroxyquinolines: A comparison of solvation models
Publisher: Royal Society of Chemistry (RSC)
Date: 2000
DOI: 10.1039/B005241H
Ionized methyl formate (CH3OCHO.ovrhdot.+) and its distonic isomer (.ovrhdot.CH2OC+HOH)
Publisher: American Chemical Society (ACS)
Date: 02-1992
DOI: 10.1021/JA00030A004
Structural Insights into the Protease-like Antigen Plasmodium falciparum SERA5 and Its Noncanonical Active-Site Serine
Publisher: Elsevier BV
Date: 09-2009
DOI: 10.1016/J.JMB.2009.07.007
Abstract: The sera genes of the malaria-causing parasite Plasmodium encode a family of unique proteins that are maximally expressed at the time of egress of parasites from infected red blood cells. These multi-domain proteins are unique, containing a central papain-like cysteine-protease fragment enclosed between the disulfide-linked N- and C-terminal domains. However, the central fragment of several members of this family, including serine repeat antigen 5 (SERA5), contains a serine (S596) in place of the active-site cysteine. Here we report the crystal structure of the central protease-like domain of Plasmodium falciparum SERA5, revealing a number of anomalies in addition to the putative nucleophilic serine: (1) the structure of the putative active site is not conducive to binding substrate in the canonical cysteine-protease manner (2) the side chain of D594 restricts access of substrate to the putative active site and (3) the S(2) specificity pocket is occupied by the side chain of Y735, reducing this site to a small depression on the protein surface. Attempts to determine the structure in complex with known inhibitors were not successful. Thus, despite having revealed its structure, the function of the catalytic domain of SERA5 remains an enigma.
Fitness and movement quality of emergency task force police officers: An age-grouped database with comparison to populations of emergency services personnel, athletes and the general public
Publisher: Elsevier BV
Date: 03-2013
Gas-phase acidities: a comparison of density functional, MP2, MP4, F4, G2(MP2, SVP), G2(MP2) and G2 procedures
Publisher: Elsevier BV
Date: 10-1995
G2(MP2,SVP) study of the relationship between the benzyl and tropyl radicals, and their cation analogues
Publisher: Elsevier BV
Date: 11-1997
Second and third trimester serum levels of HtrA1 in pregnancies affected by pre-eclampsia
Publisher: Elsevier BV
Date: 03-2021
DOI: 10.1016/J.PLACENTA.2021.02.003
Abstract: Altered placental expression of high temperature requirement factor A1 (HtrA1) is implicated in abnormal trophoblastic invasion and endothelial dysfunction in pre-ecl sia (PE). Serum levels of HtrA1 have been proposed as a novel biomarker to improve the prediction of PE. This study assesses serum HtrA1 levels in prospectively collected s les of women who developed PE compared to normotensive pregnancies. This was a case-control study of serum HtrA1 levels in second and third trimester s les in women who later developed preterm or term PE compared to controls. Overall, 300 serum s les were drawn from a prospective observational study of adverse pregnancy outcomes in three different gestational age windows (19-24, 30-34 and 35-37 weeks) at the Fetal Medicine Research Institute, King's College Hospital, London. Serum HtrA1 levels were determined by enzyme-linked immunosorbent assay (ELISA) by a blinded laboratory professional. Median HtrA1 MoM values, adjusted for gestational age and maternal characteristics, were compared between cases and controls at each gestational age group. Women who later developed PE, compared to controls, had significantly higher maternal weight and more frequently had chronic hypertension or a history of PE in a previous pregnancy. In normotensive pregnancies, serum HtrA1 increased with increasing gestational age, whereas, in PE pregnancies HtrA1 levels remained stable, but were not significantly different from control pregnancies at any gestational age. Serum HtrA1 levels are not significantly different in women who develop PE compared to controls.
Refined calculations of the structures and stabilities of the formyl (HCO+) and isoformyl (COH+) cations
Publisher: Elsevier BV
Date: 09-1992
Augmented feedback can change body shape to improve glide efficiency in swimming
Publisher: Informa UK Limited
Date: 06-04-2021
Molecular evolution of the switch for progesterone and spironolactone from mineralocorticoid receptor agonist to antagonist
Publisher: Proceedings of the National Academy of Sciences
Date: 22-08-2019
Abstract: The mineralocorticoid receptor (MR), the receptor for aldosterone, appears in evolution well before the appearance of terrestrial vertebrates, yet aldosterone emerges in vertebrates only with terrestrial life. Curiously, in fish, the MR sees progesterone and spironolactone as agonists, whereas in terrestrial species, they are antagonist at the MR. We have identified a unique single amino acid difference between the fish MR and the other vertebrate MR that mediates this switch, agonist to antagonist. This striking evolutionary event was perhaps mandatory if the appearance of aldosterone as a specific mediator of the homeostatic salt retention required for terrestrial life was to be tolerated. The conformational changes also provide insights into the structural basis of agonism versus antagonism in steroid receptors.
A Common Cross-species Function for the Double Epidermal Growth Factor-like Modules of the Highly Divergent Plasmodium Surface Proteins MSP-1 and MSP-8
Publisher: Elsevier BV
Date: 05-2004
Structural Studies of the Resistance of Influenza Virus Neuramindase to Inhibitors
Publisher: American Chemical Society (ACS)
Date: 30-04-2002
DOI: 10.1021/JM010528U
Abstract: Zanamivir and oseltamivir, specific inhibitors of influenza virus neuraminidase, have significantly different characteristics in resistance studies. In both cases resistance is known to arise through mutations in either the hemagglutinin or neuraminidase surface proteins. A new inhibitor under development by Biocryst Pharmaceuticals, BCX-1812, has both a guanidino group, as in zanamivir, and a bulky hydrophobic group, as in oseltamivir. Using influenza A/NWS/Tern/Australia/G70C/75 (H1N9), neuraminidase variants E119G and R292K have previously been selected by different inhibitors. The sensitivity of these variants to BCX-1812 has now been measured and found in both cases to be intermediate between those of zanamivir and oseltamivir. In addition, the X-ray crystal structures of the complexes of BCX-1812 with the wild type and the two mutant neuraminidases were determined. The ligand is bound in an identical manner in each structure, with a rearrangement of the side chain of E276 from its ligand-free position. A structural explanation of the mechanism of resistance of BCX-1812, relative to zanamivir and oseltamivir in particular, is provided.
Crystal Structure of a BCL-W Domain-Swapped Dimer: Implications for the Function of BCL-2 Family Proteins
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.STR.2011.07.015
Abstract: The prosurvival and proapoptotic proteins of the BCL-2 family share a similar three-dimensional fold despite their opposing functions. However, many biochemical studies highlight the requirement for conformational changes for the functioning of both types of proteins, although structural data to support such changes remain elusive. Here, we describe the X-ray structure of dimeric BCL-W that reveals a major conformational change involving helices α3 and α4 hinging away from the core of the protein. Biochemical and functional studies reveal that the α4-α5 hinge region is required for dimerization of BCL-W, and functioning of both pro- and antiapoptotic BCL-2 proteins. Hence, this structure reveals a conformational flexibility not seen in previous BCL-2 protein structures and provides insights into how these regulators of apoptosis can change conformation to exert their function.
Harmonic force field, molecular structure, torsional potential, and possible isomerism of hydrogen sulfide (H2S2)
Publisher: American Chemical Society (ACS)
Date: 1988
DOI: 10.1021/J100313A021
Apoptotic pore formation is associated with in-plane insertion of Bak or Bax central helices into the mitochondrial outer membrane
Publisher: Proceedings of the National Academy of Sciences
Date: 16-09-2014
Abstract: To trigger cell death (apoptosis), two members of the B-cell lymphoma-2 protein family, Bak and Bax, change shape and convert from inert monomers into the oligomers that disrupt the outer mitochondrial membrane, but how they perturb the membrane is poorly understood. A longstanding model is that they rearrange and insert two central helices, α5 and α6, as a hairpin through the membrane. We show, however, that the hairpin insertion model does not hold. Instead, these helices in the oligomers insert only shallowly in the membrane, in its plane. The results favor a model in which these and probably other helices of Bak and Bax crowd the outer leaflet of the membrane, producing membrane curvature that leads to its disruption.
The harmonic force field and rz molecular structure of disulphur monoxide, S2O
Publisher: Elsevier BV
Date: 03-1990
Structure-guided design of a novel class of benzyl-sulfonate inhibitors for influenza virus neuraminidase
Publisher: Portland Press Ltd.
Date: 27-09-2006
DOI: 10.1042/BJ20060447
Abstract: Influenza NA (neuraminidase) is an antiviral target of high pharmaceutical interest because of its essential role in cleaving sialic acid residues from cell surface glycoproteins and facilitating release of virions from infected cells. The present paper describes the use of structural information in the progressive design from a lead binding ion (a sulfate) to a potent submicromolor inhibitor (Ki 0.13 μM). Structural information derived from the X-ray structure of an NA complexed with several sulfate ions, in combination with results derived from affinity labelling and molecular modelling studies, was used to guide design of potent sulfonic acid-based inhibitors. These inhibitors are structural fragments of the polysulfonate triazine dye Cibacron Blue 3GA and represent novel lead scaffolds for designing non-carbohydrate inhibitors for influenza neuraminidases.
Can thioglycosides imitate the oxonium intermediate in glycosyl hydrolases?
Publisher: Elsevier BV
Date: 11-2003
The structure of the fusion glycoprotein of Newcastle disease virus suggests a novel paradigm for the molecular mechanism of membrane fusion
Publisher: Elsevier BV
Date: 03-2001
DOI: 10.1016/S0969-2126(01)00581-0
Abstract: Membrane fusion within the Paramyxoviridae family of viruses is mediated by a surface glycoprotein termed the "F", or fusion, protein. Membrane fusion is assumed to involve a series of structural transitions of F from a metastable (prefusion) state to a highly stable (postfusion) state. No detail is available at the atomic level regarding the metastable form of these proteins or regarding the transitions accompanying fusion. The three-dimensional structure of the fusion protein of Newcastle disease virus (NDV-F) has been determined. The trimeric NDV-F molecule is organized into head, neck, and stalk regions. The head is comprised of a highly twisted beta domain and an additional immunoglobulin-like beta domain. The neck is formed by the C-terminal extension of the heptad repeat region HR-A, capped by a four-helical bundle. The C terminus of HR-A is encased by a further helix HR-C and a 4-stranded beta sheet. The stalk is formed by the remaining visible portion of HR-A and by polypeptide immediately N-terminal to the C-terminal heptad repeat region HR-B. An axial channel extends through the head and neck and is fenestrated by three large radial channels located approximately at the head-neck interface. We propose that prior to fusion activation, the hydrophobic fusion peptides in NDV-F are sequestered within the radial channels within the head, with the central HR-A coiled coil being only partly formed. Fusion activation then involves, inter alia, the assembly of a complete HR-A coiled coil, with the fusion peptides and transmembrane anchors being brought into close proximity. The structure of NDV-F is fundamentally different than that of influenza virus hemagglutinin, in that the central coiled coil is in the opposite orientation with respect to the viral membrane.
Quantification of swimmers’ ability to apply force in the water: the potential role of two new variables during tethered swimming
Publisher: Informa UK Limited
Date: 17-06-2022
DOI: 10.1080/14763141.2022.2089220
Abstract: This study aimed 1) to examine variables that may quantify the ability to apply force in the water and 2) to test their relationship with free swimming performance. Sixteen regional-level swimmers participated in this study. Average (F
The Segmental Movements in Front Crawl Swimming
Publisher: Springer International Publishing
Date: 2018
Physiological restraint of Bak by Bcl-xL is essential for cell survival
Publisher: Cold Spring Harbor Laboratory
Date: 15-05-2016
Abstract: Due to the myriad interactions between prosurvival and proapoptotic members of the Bcl-2 family of proteins, establishing the mechanisms that regulate the intrinsic apoptotic pathway has proven challenging. Mechanistic insights have primarily been gleaned from in vitro studies because genetic approaches in mammals that produce unambiguous data are difficult to design. Here we describe a mutation in mouse and human Bak that specifically disrupts its interaction with the prosurvival protein Bcl-x L . Substitution of Glu75 in mBak (hBAK Q77) for leucine does not affect the three-dimensional structure of Bak or killing activity but reduces its affinity for Bcl-x L via loss of a single hydrogen bond. Using this mutant, we investigated the requirement for physical restraint of Bak by Bcl-x L in apoptotic regulation. In vitro, Bak Q75L cells were significantly more sensitive to various apoptotic stimuli. In vivo, loss of Bcl-x L binding to Bak led to significant defects in T-cell and blood platelet survival. Thus, we provide the first definitive in vivo evidence that prosurvival proteins maintain cellular viability by interacting with and inhibiting Bak.
Transition structures for the interchange of hydrogen atoms within the water dimer
Publisher: AIP Publishing
Date: 15-01-1990
DOI: 10.1063/1.458133
Abstract: High levels of ab initio molecular orbital theory were used to examine rearrangement processes in the water dimer corresponding to the interchange of various hydrogen atoms. Our most reliable calculations involve MP4/6-311+G(2df,2p) energy evaluations at MP2/6-311+G(d,p) optimized structures. The lowest energy rearrangement pathway corresponds to the interchange of hydrogen atoms of the acceptor molecule within the Cs water dimer structure (1). This proceeds via a transition structure of C1 symmetry (2) and requires an energy of 0.59 kcal mol−1. The interchange of donor and acceptor molecules can be achieved via a transition structure with Ci symmetry (4) and requires an energy of 0.87 kcal mol−1. Finally, the interchange of hydrogen atoms of the donor molecule, via a C2v transition structure (9), requires 1.88 kcal mol−1. The rearrangements via 2 and 4 lead to complete scrambling of hydrogen atoms within the in idual H2O moieties at a cost of 0.87 kcal mol−1 the transition structure 9 is not necessary for this process. The implications of these results with regard to the interpretation of spectroscopic data on the water dimer will be of interest.
Novel Conotoxins from Conus striatus and Conus kinoshitai Selectively Block TTX-Resistant Sodium Channels
Publisher: American Chemical Society (ACS)
Date: 21-04-2005
DOI: 10.1021/BI0473408
Abstract: The peptides isolated from venoms of predatory marine Conus snails ("conotoxins") are well-known to be highly potent and selective pharmacological agents for voltage-gated ion channels and receptors. We report the discovery of two novel TTX-resistant sodium channel blockers, mu-conotoxins SIIIA and KIIIA, from two species of cone snails. The two toxins were identified and characterized by combining molecular techniques and chemical synthesis. Both peptides inhibit TTX-resistant sodium currents in neurons of frog sympathetic and dorsal root ganglia but poorly block action potentials in frog skeletal muscle, which are mediated by TTX-sensitive sodium channels. The amino acid sequences in the C-terminal region of the two peptides and of the previously characterized mu-conotoxin SmIIIA (which also blocks TTX-resistant channels) are similar, but the three peptides differ in the length of their first N-terminal loop. We used molecular dynamics simulations to analyze how altering the number of residues in the first loop affects the overall structure of mu-conotoxins. Our results suggest that the naturally occurring truncations do not affect the conformation of the C-terminal loops. Taken together, structural and functional differences among mu-conotoxins SmIIIA, SIIIA, and KIIIA offer a unique insight into the "evolutionary engineering" of conotoxin activity.
Lactam-Stabilized Helical Analogues of the Analgesic μ-Conotoxin KIIIA
Publisher: American Chemical Society (ACS)
Date: 12-10-2011
DOI: 10.1021/JM200839A
Evaluation of accurate gas-phase acidities
Publisher: American Chemical Society (ACS)
Date: 12-1991
DOI: 10.1021/J100179A009
Predicting Performance and Injury Resilience From Movement Quality and Fitness Scores in a Basketball Team Over 2 Years
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2012
Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity
Publisher: American Chemical Society (ACS)
Date: 08-09-2014
DOI: 10.1021/ML5001867
Dissociation of reward and effort sensitivity in methcathinone‐induced Parkinsonism
Publisher: Wiley
Date: 05-04-2018
DOI: 10.1111/JNP.12122
Characterization of the bifurcated structure of the water dimer
Publisher: AIP Publishing
Date: 08-1991
DOI: 10.1063/1.461030
Abstract: The bifurcated structure of the water dimer has been the subject of considerable uncertainty with respect to its vibrational characterization. We have considered this question at the self-consistent-field (SCF) level of theory using finite basis sets that allow a close approach to the Hartree–Fock limit. As one approaches the Hartree–Fock limit, the bifurcated structure is predicted to be a true transition state, with one imaginary vibrational frequency, ω12(B2)∼200i cm−1.
Single-chain insulin analogs threaded by the insulin receptor αCT domain
Publisher: Elsevier BV
Date: 11-2022
Evaluating the intra- and inter-day reliability of output measures for the VALD HumanTrak: dynamic movements and range of motion of the shoulder and hip with body armour
Publisher: Informa UK Limited
Date: 20-07-2023
DOI: 10.1080/00140139.2022.2092218
Abstract: The HumanTrak captures human movement through markerless motion tracking and can be a crucial tool in military physical screening. Reliability was examined in eighteen healthy participants who completed shoulder and hip ROM, and dynamic tasks in three body armour conditions. Generally, for all conditions, good to excellent reliability was observed in shoulder abduction and flexion, hip abduction and adduction, and dynamic squats knee and hip flexion (ICC ≥ 0.75 excluding outliers). Shoulder adduction and hip flexion demonstrated moderate to excellent reliability (ICC ≥ 0.50). Shoulder and hip extension and the drop jump were unreliable (ICC: 0.10-0.94, 0.15-0.89, and 0.30-0.82, respectively) due to the large distribution of ICC scores. Tasks with ROM values ≥ 100° involving movement towards or perpendicular to the HumanTrak camera tended to have greater reliability than movements moving away from the camera and out of the perpendicular plane regardless if body armour was worn.
Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis
Publisher: Springer Science and Business Media LLC
Date: 21-06-2018
DOI: 10.1038/S41467-018-04714-7
Abstract: Necroptotic cell death is mediated by the most terminal known effector of the pathway, MLKL. Precisely how phosphorylation of the MLKL pseudokinase domain activation loop by the upstream kinase, RIPK3, induces unmasking of the N-terminal executioner four-helix bundle (4HB) domain of MLKL, higher-order assemblies, and permeabilization of plasma membranes remains poorly understood. Here, we reveal the existence of a basal monomeric MLKL conformer present in human cells prior to exposure to a necroptotic stimulus. Following activation, toggling within the MLKL pseudokinase domain promotes 4HB domain disengagement from the pseudokinase domain αC helix and pseudocatalytic loop, to enable formation of a necroptosis-inducing tetramer. In contrast to mouse MLKL, substitution of RIPK3 substrate sites in the human MLKL pseudokinase domain completely abrogated necroptotic signaling. Therefore, while the pseudokinase domains of mouse and human MLKL function as molecular switches to control MLKL activation, the underlying mechanism differs between species.
A minimized human insulin-receptor-binding motif revealed in a Conus geographus venom insulin
Publisher: Springer Science and Business Media LLC
Date: 12-09-2016
DOI: 10.1038/NSMB.3292
Abstract: Insulins in the venom of certain fish-hunting cone snails facilitate prey capture by rapidly inducing hypoglycemic shock. One such insulin, Conus geographus G1 (Con-Ins G1), is the smallest known insulin found in nature and lacks the C-terminal segment of the B chain that, in human insulin, mediates engagement of the insulin receptor and assembly of the hormone's hexameric storage form. Removal of this segment (residues B23-B30) in human insulin results in substantial loss of receptor affinity. Here, we found that Con-Ins G1 is monomeric, strongly binds the human insulin receptor and activates receptor signaling. Con-Ins G1 thus is a naturally occurring B-chain-minimized mimetic of human insulin. Our crystal structure of Con-Ins G1 reveals a tertiary structure highly similar to that of human insulin and indicates how Con-Ins G1's lack of an equivalent to the key receptor-engaging residue Phe
Analysis of inhibitor binding in influenza virus neuraminidase
Publisher: Wiley
Date: 04-2001
DOI: 10.1110/PS.41801
Abstract: 2,3-didehydro-2-deoxy-N:-acetylneuraminic acid (DANA) is a transition state analog inhibitor of influenza virus neuraminidase (NA). Replacement of the hydroxyl at the C9 position in DANA and 4-amino-DANA with an amine group, with the intention of taking advantage of an increased electrostatic interaction with a conserved acidic group in the active site to improve inhibitor binding, significantly reduces the inhibitor activity of both compounds. The three-dimensional X-ray structure of the complexes of these ligands and NA was obtained to 1.4 A resolution and showed that both ligands bind isosterically to DANA. Analysis of the geometry of the ammonium at the C4 position indicates that Glu119 may be neutral when these ligands bind. A computational analysis of the binding energies indicates that the substitution is successful in increasing the energy of interaction however, the gains that are made are not sufficient to overcome the energy that is required to desolvate that part of the ligand that comes in contact with the protein.
Differences in the determinants of eplerenone, spironolactone and aldosterone binding to the mineralocorticoid receptor
Publisher: Wiley
Date: 10-2004
DOI: 10.1111/J.1440-1681.2004.04079.X
Abstract: The importance of mineralocorticoid receptor (MR) antagonists in the treatment of cardiovascular disease has been emphasised by two recent clinical trials, one using spironolactone and the other using a new selective MR antagonist, namely eplerenone. Eplerenone has a very low affinity for the glucocorticoid receptor (GR). Determinants of binding specificity of eplerenone to the MR were investigated using chimeras created between the ligand-binding domains (LBD) of the MR and the GR. These chimeras had been used previously to investigate aldosterone and spironolactone binding specificity to the MR. Eplerenone competed strongly for [(3)H]-dexamethasone binding to a MR/GR chimera containing amino acids 804-874 of the MR and weakly to a chimera containing amino acids 672-803 of the MR. Within the 804-874 region, eplerenone competed for [(3)H]-dexamethasone binding to a chimera containing amino acids 820-844 of the MR, although the calculated affinity was approximately 10-fold lower than for binding to the full-length MR LBD. Similar results were obtained using another MR antagonist, namely spironolactone. Modelling of eplerenone binding to the MR LBD, based on the GR LBD crystal structure, suggests that amino acids 820-844 affect the overall shape of the ligand-binding pocket and that eplerenone acts as an MR antagonist because it fails to stabilize the active conformation of the receptor. In contrast with results with the MR antagonists eplerenone and spironolactone, amino acids 820-844 are sufficient in themselves to confer high-affinity aldosterone binding to the MR, suggesting that the binding determinants of the two antagonists are similar to each other but differ from those of aldosterone.
Substrate-Assisted Catalysis in Sialic Acid Aldolase
Publisher: American Chemical Society (ACS)
Date: 20-01-1999
DOI: 10.1021/JO981960V
Abstract: Sialic acid aldolase catalyses the reversible aldol condensation of pyruvate and N-acetylmannosamine with an apparent lack of stereospecificity. Consistent with this, modeling of Schiff base and enamine intermediates in the active site of this enzyme yields two conformations, corresponding to si- and re-face attack in the aldol condensation reaction. The acceptor-aldehyde group is found on different sides of the enamine in the two conformations, but with the remainder of the substrate having very similar geometries in the protein. No histidine residue previously speculated to function as a general base in the mechanism is found near the enzyme active site. In the absence of functionally active groups in the active site, the carboxylate of the substrate is proposed to function as the general acid/base. Molecular orbital calculations indicate that the barrier to aldol cleavage via this mechanism in the gas phase of the related system, 4-hydroxy-2-methyiminopentanoic acid, is 74 kJ mol(-)(1).
Is torso twist production the primary role of the torso muscles in front crawl swimming?
Publisher: Informa UK Limited
Date: 18-05-2021
Sustainable Syntheses of (−)-Jerantinines A & E and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site
Publisher: Springer Science and Business Media LLC
Date: 13-07-2018
DOI: 10.1038/S41598-018-28880-2
Abstract: The jerantinine family of Aspidosperma indole alkaloids from Tabernaemontana corymbosa are potent microtubule-targeting agents with broad spectrum anticancer activity. The natural supply of these precious metabolites has been significantly disrupted due to the inclusion of T. corymbosa on the endangered list of threatened species by the International Union for Conservation of Nature. This report describes the asymmetric syntheses of (−)-jerantinines A and E from sustainably sourced (−)-tabersonine, using a straight-forward and robust biomimetic approach. Biological investigations of synthetic (−)-jerantinine A, along with molecular modelling and X-ray crystallography studies of the tubulin—(−)-jerantinine B acetate complex, advocate an anticancer mode of action of the jerantinines operating via microtubule disruption resulting from binding at the colchicine site. This work lays the foundation for accessing useful quantities of enantiomerically pure jerantinine alkaloids for future development.
A lethal fungal pathogen directly alters tight junction proteins in the skin of a susceptible amphibian
Publisher: The Company of Biologists
Date: 2018
DOI: 10.1242/JEB.192245
Abstract: Bacterial and viral pathogens can weaken epithelial barriers by targeting and disrupting tight junction (TJ) proteins. Comparatively, however, little is known about the direct effects of fungal pathogens on TJ proteins and their expression. The disease, chytridiomycosis, caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd), is threatening hibian populations worldwide. Bd is known to infect hibian skin and disrupt cutaneous osmoregulation. However, exactly how this occurs is poorly understood. This study considered the impact of Bd infection on the barrier properties of the Australian green tree frog (Litoria caerulea) epidermis by examining how inoculation of animals with Bd influenced the paracellular movement of FITC-dextran (4 kDa, FD-4) across the skin in association with alterations in the mRNA and protein abundance of select TJ proteins of the epidermal TJ complex. It was observed that Bd infection increased paracellular movement of FD-4 across the skin linearly with fungal infection load. In addition, Bd infection increased transcript abundance of the tricellular TJ (tTJ) protein tricellulin (tric) as well as the bicellular TJ (bTJ) proteins occludin (ocln), claudin (cldn) -1, -4 and the scaffolding TJ protein zonula occludens-1 (zo-1). However, while Tric protein abundance increased in accord with changes in transcript abundance, protein abundance of Cldn-1 was significantly reduced and Ocln protein abundance was unchanged. Data indicate that disruption of cutaneous osmoregulation in L. caerulea following Bd infection occurs, at least in part, by an increase in epidermal paracellular permeability in association with compromised integrity of the epidermal TJ complex.
“Register-shift” insulin analogs uncover constraints of proteotoxicity in protein evolution
Publisher: Elsevier BV
Date: 03-2020
Structural basis for plasmepsin V inhibition that blocks export of malaria proteins to human erythrocytes
Publisher: Springer Science and Business Media LLC
Date: 27-07-2015
DOI: 10.1038/NSMB.3061
Abstract: Plasmepsin V, an essential aspartyl protease of malaria parasites, has a key role in the export of effector proteins to parasite-infected erythrocytes. Consequently, it is an important drug target for the two most virulent malaria parasites of humans, Plasmodium falciparum and Plasmodium vivax. We developed a potent inhibitor of plasmepsin V, called WEHI-842, which directly mimics the Plasmodium export element (PEXEL). WEHI-842 inhibits recombinant plasmepsin V with a half-maximal inhibitory concentration of 0.2 nM, efficiently blocks protein export and inhibits parasite growth. We obtained the structure of P. vivax plasmepsin V in complex with WEHI-842 to 2.4-Å resolution, which provides an explanation for the strict requirements for substrate and inhibitor binding. The structure characterizes both a plant-like fold and a malaria-specific helix-turn-helix motif that are likely to be important in cleavage of effector substrates for export.
Engineering a Stable and Selective Peptide Blocker of the Kv1.3 Channel in T Lymphocytes
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 02-01-2009
Neutralization-reionization and ab initio study of the CH2CHSOH ⇄ CH3CHSO rearrangement
Publisher: Elsevier BV
Date: 12-1990
Specificity and Promiscuity in Protein - Ligand and Protein - Protein Interactions
Publisher: CSIRO Publishing
Date: 2003
DOI: 10.1071/CH03020
De-novo designed library of benzoylureas as inhibitors of BCL-XL: synthesis, structural and biochemical characterization.
Publisher: American Chemical Society (ACS)
Date: 05-02-2014
DOI: 10.1021/JM401948B
Aromatic Anchor at an Invariant Hormone-Receptor Interface
Publisher: Elsevier BV
Date: 12-2014
Refined thermochemistry for the methanol radical cation (CH3OH.cntdot.+) and its distonic isomer (CH2OH2.cntdot.+)
Publisher: American Chemical Society (ACS)
Date: 07-1992
DOI: 10.1021/J100193A029
Structural analysis of phosphorylation-associated interactions of human MCC with Scribble PDZ domains.
Publisher: Wiley
Date: 30-07-2019
DOI: 10.1111/FEBS.15002
Abstract: Scribble is a crucial adaptor protein that plays a pivotal role during establishment and control of cell polarity, impacting many physiological processes ranging from cell migration to immunity and organization of tissue architecture. Scribble harbours a leucine-rich repeat domain and four PDZ domains that mediate most of Scribble's interactions with other proteins. It has become increasingly clear that post-translational modifications substantially impact Scribble-ligand interactions, with phosphorylation being a major modulator of binding to Scribble. To better understand how Scribble PDZ domains direct cell polarity signalling and how phosphorylation impacts this process, we investigated human Scribble interactions with MCC (Mutated in Colorectal Cancer). We systematically evaluated the ability of all four in idual Scribble PDZ domains to bind the PDZ-binding motif (PBM) of MCC as well as MCC phosphorylated at the -1 Ser position. We show that Scribble PDZ1 and PDZ3 are the major interactors with MCC, and that modifications to Ser at the -1 position in the MCC PBM only has a minor effect on binding to Scribble PDZ domains. We then examined the structural basis for these observations by determining the crystal structures of Scribble PDZ1 domain bound to both the unphosphorylated MCC PBM as well as phosphorylated MCC. Our structures indicated that phospho-Ser at the -1 position in MCC is not involved in major contacts with Scribble PDZ1, and in conjunction with our affinity measurements suggest that the impact of phosphorylation at the -1 position of MCC must extend beyond a simple modulation of the affinity for Scribble PDZ domains.
A structurally minimized yet fully active insulin based on cone-snail venom insulin principles
Publisher: Springer Science and Business Media LLC
Date: 06-2020
Structural basis of Bcl-xL recognition by a BH3-mimetic α/β-peptide generated by sequence-based design.
Publisher: Wiley
Date: 08-07-2011
Ab initio molecular orbital calculations on sulphur compounds
Publisher: Elsevier BV
Date: 12-1983
Structural Basis for Broad Substrate Specificity in Higher Plant β-d-Glucan Glucohydrolases
Publisher: Oxford University Press (OUP)
Date: 05-2002
DOI: 10.1105/TPC.010442
Abstract: Family 3 beta-D-glucan glucohydrolases are distributed widely in higher plants. The enzymes catalyze the hydrolytic removal of beta-D-glucosyl residues from nonreducing termini of a range of beta-D-glucans and beta-D-oligoglucosides. Their broad specificity can be explained by x-ray crystallographic data obtained from a barley beta-D-glucan glucohydrolase in complex with nonhydrolyzable S-glycoside substrate analogs and by molecular modeling of enzyme/substrate complexes. The glucosyl residue that occupies binding subsite -1 is locked tightly into a fixed position through extensive hydrogen bonding with six amino acid residues near the bottom of an active site pocket. In contrast, the glucosyl residue at subsite +1 is located between two Trp residues at the entrance of the pocket, where it is constrained less tightly. The relative flexibility of binding at subsite +1, coupled with the projection of the remainder of bound substrate away from the enzyme's surface, means that the overall active site can accommodate a range of substrates with variable spatial dispositions of adjacent beta-D-glucosyl residues. The broad specificity for glycosidic linkage type enables the enzyme to perform erse functions during plant development.
A Family of Leukemia Inhibitory Factor-Binding Peptides that Can Act as Antagonists When Conjugated to Poly(ethylene glycol)
Publisher: American Chemical Society (ACS)
Date: 22-10-2003
DOI: 10.1021/BI035303V
Abstract: A panel of six naïve 14-residue random peptide libraries displayed polyvalently on M13 phage was pooled and sorted against human leukemia inhibitory factor (LIF). After four rounds of selection, a single large family of peptides with the consensus sequence XCXXXXG(A/S)(D/E)(W/F)WXCF was found to bind specifically to LIF. Peptides within this family did not bind related members of the interleukin-6 family of cytokines, nor to murine LIF that has 80% sequence identity with human LIF. A representative peptide from this family was synthesized and found to bind to LIF with an affinity of approximately 300 nM. The phage-displayed form of this peptide was able to compete with the LIF receptor alpha chain (LIFR) for binding to LIF however, the free synthetic peptide was unable to inhibit LIF-LIFR binding or inhibit LIF bioactivity in vitro. Using a panel of human/murine chimeric LIF molecules, the peptide-binding site on LIF was mapped to a groove located between the B and the C helices of the LIF structure, which is distinct from the surfaces involved in binding to receptor. To mimic the effect of the phage particle and convert the free peptide into an antagonist of LIFR binding, a 40 kDa poly(ethylene glycol) (PEG) moiety was conjugated to the synthetic LIF-binding peptide. This PEG-peptide conjugate was found to be both an antagonist of LIF-LIFR binding and of LIF signaling in engineered Ba/F3 cells expressing LIFR and the gp130 coreceptor.
Structure–Activity Relationship Study Reveals the Molecular Basis for Specific Sensing of Hydrophobic Amino Acids by the Campylobacter jejuni Chemoreceptor Tlp3
Publisher: MDPI AG
Date: 11-05-2020
DOI: 10.3390/BIOM10050744
Abstract: Chemotaxis is an important virulence factor of the foodborne pathogen C ylobacter jejuni. Inactivation of chemoreceptor Tlp3 reduces the ability of C. jejuni to invade human and chicken cells and to colonise the jejunal mucosa of mice. Knowledge of the structure of the ligand-binding domain (LBD) of Tlp3 in complex with its ligands is essential for a full understanding of the molecular recognition underpinning chemotaxis. To date, the only structure in complex with a signal molecule is Tlp3 LBD bound to isoleucine. Here, we used in vitro and in silico screening to identify eight additional small molecules that signal through Tlp3 as attractants by directly binding to its LBD, and determined the crystal structures of their complexes. All new ligands (leucine, valine, α-amino-N-valeric acid, 4-methylisoleucine, β-methylnorleucine, 3-methylisoleucine, alanine, and phenylalanine) are nonpolar amino acids chemically and structurally similar to isoleucine. X-ray crystallographic analysis revealed the hydrophobic side-chain binding pocket and conserved protein residues that interact with the ammonium and carboxylate groups of the ligands determine the specificity of this chemoreceptor. The uptake of hydrophobic amino acids plays an important role in intestinal colonisation by C. jejuni, and our study suggests that C. jejuni seeks out hydrophobic amino acids using chemotaxis.
Novel Conotoxins from Conus striatus and Conus kinoshitai Selectively Block TTX-Resistant Sodium Channels
Publisher: American Chemical Society (ACS)
Date: 08-02-2006
DOI: 10.1021/BI068001C
The SPRY domain of SSB-2 adopts a novel fold that presents conserved Par-4-binding residues
Publisher: Springer Science and Business Media LLC
Date: 20-12-2006
DOI: 10.1038/NSMB1034
Abstract: The four mammalian SPRY domain-containing SOCS box proteins (SSB-1 to SSB-4) are characterized by a C-terminal SOCS box and a central SPRY domain. We have determined the first SPRY-domain structure, as part of SSB-2, by NMR. This domain adopts a novel fold consisting of a beta-sandwich structure formed by two four-stranded antiparallel beta-sheets with a unique topology. We demonstrate that SSB-1, SSB-2 and SSB-4, but not SSB-3, bind prostate apoptosis response protein-4 (Par-4). Mutational analysis of SSB-2 loop regions identified conserved structural determinants for its interaction with Par-4 and the hepatocyte growth factor receptor, c-Met. Mutations in analogous loop regions of pyrin and midline-1 SPRY domains have been shown to cause Mediterranean fever and Opitz syndrome, respectively. Our findings provide a template for SPRY-domain structure and an insight into the mechanism of SPRY-protein interaction.
Ethynol: a theoretical prediction of remarkably high gas-phase acidity
Publisher: American Chemical Society (ACS)
Date: 10-1989
DOI: 10.1021/JA00203A051
Ethynamine: the remarkable acid-strengthening and base-weakening effect of the acetylenic linkage. A comparison with ethenamine and methylamine
Publisher: American Chemical Society (ACS)
Date: 1992
DOI: 10.1021/JA00027A004
Higher-Resolution Structure of the Human Insulin Receptor Ectodomain: Multi-Modal Inclusion of the Insert Domain
Publisher: Elsevier BV
Date: 03-2016
BioPPSy: An Open-Source Platform for QSAR/QSPR Analysis
Publisher: Public Library of Science (PLoS)
Date: 10-11-2016
α/β-Peptide Foldamers Targeting Intracellular Protein–Protein Interactions with Activity in Living Cells
Publisher: American Chemical Society (ACS)
Date: 28-08-2015
DOI: 10.1021/JACS.5B05896
Ion currents through Kir potassium channels are gated by anionic lipids
Publisher: Springer Science and Business Media LLC
Date: 25-01-2022
DOI: 10.1038/S41467-022-28148-4
Abstract: Ion currents through potassium channels are gated. Constriction of the ion conduction pathway at the inner helix bundle, the textbook gate of Kir potassium channels, has been shown to be an ineffective permeation control, creating a rift in our understanding of how these channels are gated. Here we present evidence that anionic lipids act as interactive response elements sufficient to gate potassium conduction. We demonstrate the limiting barrier to K + permeation lies within the ion conduction pathway and show that this gate is operated by the fatty acyl tails of lipids that infiltrate the conduction pathway via fenestrations in the walls of the pore. Acyl tails occupying a surface groove extending from the cytosolic interface to the conduction pathway provide a potential means of relaying cellular signals, mediated by anionic lipid head groups bound at the canonical lipid binding site, to the internal gate.
Interaction of small ionic species with phospholipid membranes: The role of metal coordination
Publisher: Frontiers Media SA
Date: 07-01-2019
Isomers and transition structures of diazene
Publisher: American Chemical Society (ACS)
Date: 10-1993
DOI: 10.1021/J100143A001
How insulin engages its primary binding site on the insulin receptor
Publisher: Springer Science and Business Media LLC
Date: 2013
DOI: 10.1038/NATURE11781
The cyclization of N-butylpent-4-enylaminyl revisited: a combined theoretical and experimental study †
Publisher: Royal Society of Chemistry (RSC)
Date: 2000
DOI: 10.1039/A909747C
Cortisol resistance in the New World revisited
Publisher: Elsevier BV
Date: 09-2004
Low back loads while walking and carrying: comparing the load carried in one hand or in both hands
Publisher: Informa UK Limited
Date: 02-2013
DOI: 10.1080/00140139.2012.752528
Abstract: This study investigates the consequences of carrying load in one hand versus both hands. Six participants walked carrying buckets containing various weights. The weight was either carried in one hand or distributed evenly between both hands. Electromyography, force plate and body kinematic data were input to a three-dimensional anatomically detailed model of the spine to calculate spine loading. Carrying loads in one hand resulted in more load on the low back than when the load was split between both hands. When carrying 30 kg in one hand, the low back compression exceeded 2800 N however, splitting the load between hands reduced low back compression to 1570 N (reduction of 44%). Doubling the total load by carrying 30 kg in each hand actually produced lower spine compression than when carrying 30 kg in one hand. Balancing the load between both hands when carrying material has merit and should be considered when designing work. Carrying a load in one hand (30 kg) resulted in more spine load than splitting the same load between both hands (15 kg). When carrying double the load in both hands (30 kg in each hand vs. 30 kg in one hand), spine load decreased, suggesting merit in balancing load when designing work.
Understanding the effects of training on underwater undulatory swimming performance and kinematics
Publisher: Informa UK Limited
Date: 04-03-2021
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