ORCID Profile
0000-0001-9988-6152
Current Organisation
University of Queensland
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Medicinal and Biomolecular Chemistry | Biomolecular Modelling and Design | Macromolecular and Materials Chemistry | Crop and Pasture Protection (Pests, Diseases and Weeds) | Biologically Active Molecules | Crop and Pasture Production | Medical Biotechnology | Macromolecular Design | Plant Protection (Pests, Diseases And Weeds) | Receptors and Membrane Biology |
Environmentally Sustainable Plant Production not elsewhere classified | Control of Plant Pests, Diseases and Exotic Species in Farmland, Arable Cropland and Permanent Cropland Environments | Expanding Knowledge in the Chemical Sciences | Expanding Knowledge in the Biological Sciences | Treatments (e.g. chemicals, antibiotics) | Crop and animal protection chemicals | Biological sciences | Expanding Knowledge in the Medical and Health Sciences | Food Safety
Publisher: American Chemical Society (ACS)
Date: 21-05-2020
Publisher: MDPI AG
Date: 11-06-2015
Publisher: Elsevier BV
Date: 05-2013
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8SC01423J
Abstract: Chemical shifts can be used to predict the conformation of disulfide bonds, greatly improving resolution of solution NMR structures.
Publisher: Proceedings of the National Academy of Sciences
Date: 09-08-2010
Abstract: Plants produce a variety of proteinase inhibitors (PIs) that have a major function in defense against insect herbivores. In turn, insects have developed strategies to minimize the effect of dietary PIs on digestion. We have discovered that Helicoverpa larvae that survive consumption of a multidomain serine PI from Nicotiana alata (NaPI) contain high levels of a chymotrypsin that is not inhibited by NaPI. Here we describe the isolation of this NaPI-resistant chymotrypsin and an NaPI-susceptible chymotrypsin from Helicoverpa larvae, together with their corresponding cDNAs. We investigated the mechanism of resistance by mutating selected positions of the NaPI-susceptible chymotrypsin using the corresponding amino acids of the NaPI-resistant chymotrypsin. Four critical residues that conferred resistance to NaPI were identified. Molecular modeling revealed that a Phe→Leu substitution at position 37 in the chymotrypsin results in the loss of important binding contacts with NaPI. Identification of the molecular mechanisms that contribute to PI resistance in insect digestive proteases will enable us to develop better inhibitors for the control of lepidopteran species that are major agricultural pests worldwide.
Publisher: American Chemical Society (ACS)
Date: 23-08-2002
DOI: 10.1021/BI025744Z
Abstract: The [des(17-21)]-endothelin-1 (CSH-ET) and [Lys(-)(2)-Arg(-)(1)-des(17-21)]-endothelin-1 (KR-CSH-ET) peptides, designed by removing the five-residue hydrophobic tail from the endothelin-1 (ET-1) and [Lys(-)(2)-Arg(-)(1)]-endothelin-1 (KR-ET-1) peptides, respectively, were synthesized. Previous studies on KR-ET-1 showed that, in contrast to ET-1, this engineered compound displays a pH-dependent conformational change related to the formation of a stabilizing salt bridge between the Arg(-)(1) and Asp(8) side chains. CD and NMR spectra indicate that CSH-ET and KR-CSH-ET display conformational behavior similar to those of ET-1 and KR-ET-1, respectively. The short salt bridge-stabilized KR-CSH-ET peptide therefore appears to be an attractive elementary scaffold for drug design. The solution structure of the salt-bridged form of KR-CSH-ET was determined by NMR at pH 4.5 and is very similar to the corresponding form of the parent KR-ET-1 peptide. Molecular dynamics simulations of the salt-bridged form of KR-CSH-ET were performed using both the GB/SA implicit solvation scheme or an explicit solvation and the particle-mesh Ewald method for long-range electrostatic calculation. Unexpectedly, the Arg(-)(1)-Asp(8) salt bridge does not display in the simulation the stability that could be expected from the experimental data. The cooperative involvement of a cation-pi interaction in formation of the salt bridge has been hypothesized. Difficulties in accurately simulating cation-pi interactions might be responsible for the lack of stability in the simulation. At this time, however, no definitive explanation for the observed discrepancy between experiments and simulations is available, and further experimental studies appear to be necessary to fully understand in atomic detail the pH-dependent conformational change observed in the KR-ET-1 series.
Publisher: Oxford University Press (OUP)
Date: 17-11-2009
DOI: 10.1093/NAR/GKP946
Publisher: Oxford University Press (OUP)
Date: 23-12-2008
DOI: 10.1093/NAR/GKM953
Publisher: Public Library of Science (PLoS)
Date: 03-03-2011
Publisher: American Chemical Society (ACS)
Date: 27-01-2020
DOI: 10.1021/ACS.JMEDCHEM.9B01409
Abstract: αO-conotoxin GeXIVA from
Publisher: Elsevier BV
Date: 03-2012
DOI: 10.1016/J.TOXICON.2010.12.003
Abstract: Conotoxins are disulfide-rich peptides from the venoms of marine cone snails that are used in prey capture. Due to their exquisite potency and selectivity for different ion channels, receptors and transporters they have attracted much interest as leads in drug design. This article gives a brief background on conotoxins, describes their structures and highlights methods for synthetic cyclization to improve their biopharmaceutical properties. The proximity of the N and C termini of many conotoxins makes them particularly suitable for cyclization with linkers of on average five to seven amino acids. By linking the ends of conotoxins it is possible to significantly decrease their susceptibility to proteolysis without loss of their intrinsic biological activity. Here, the principles of conotoxin cyclization are illustrated with applications to the α- and χ- conotoxin classes, which have been implicated as leads for the treatment of pain and a range of other disorders including neuroprotection, schizophrenia, depression and cancer.
Publisher: Oxford University Press (OUP)
Date: 06-12-2008
DOI: 10.1093/BIOINFORMATICS/BTM596
Abstract: Summary: ConoServer is a new database dedicated to conopeptides, a large family of peptides found in the venom of marine snails of the genus Conus. These peptides have an exceptional ersity of sequences and chemical modifications and their ability to block ion channels makes them important as drug leads and tools for physiological studies. ConoServer uses standardized names and a genetic and structural classification scheme to present data retrieved from SwissProt, GenBank, the Protein DataBank and the literature. The ConoServer web site incorporates specialized features like the graphic display of post-translational modifications that are extensively present in conopeptides. Currently, ConoServer manages 1214 nucleic sequences (from 54 Conus species), 2258 proteic sequences (from 66 Conus species) and 99 3D structures. Availability: research1t.imb.uq.edu.au/conoserver/ Contact: d.craik@imb.uq.edu.au
Publisher: Elsevier BV
Date: 04-2022
Publisher: Wiley
Date: 07-06-2019
DOI: 10.1111/BPH.14698
Publisher: Wiley
Date: 07-03-2014
Publisher: Wiley
Date: 26-10-2020
DOI: 10.1002/PEP2.24209
Abstract: Melanocortin receptors are pharmaceutically important receptors that are involved in complex physiological functions. They have been associated with various diseases including obesity, erectile dysfunction, acne, and skin cancer. It has been challenging to transform nonselective endogenous agonist and antagonist ligands into selective and potent ligands. In this study, we investigated naturally occurring peptides derived from frog skin secretions for selectivity and activity toward melanocortin receptors. Three peptides (ORB, ORB2K and ranacyclin‐T) were found to have selectivity towards the melanocortin receptor 5 (MC5R). ORB and ORB2K had partial binding affinity at nanomolar concentrations, whereas ranacyclin‐T had 57% binding efficiency at 1.6 μM. Backbone cyclization of ORB and ORB2K altered the binding efficiency to melanocortin receptors. Our results suggest that these frog‐skin peptides could be modified for developing melanocortin‐specific ligands and potentially future therapeutics.
Publisher: AIP Publishing
Date: 08-2019
DOI: 10.1063/1.5098794
Abstract: Single-photon emitters in gallium nitride (GaN) are gaining interest as attractive quantum systems due to the well-established techniques for growth and nanofabrication of the host material, as well as its remarkable chemical stability and optoelectronic properties. We investigate the nature of such single-photon emitters in GaN with a systematic analysis of various s les produced under different growth conditions. We explore the effect that intrinsic structural defects (dislocations and stacking faults), doping, and crystal orientation in GaN have on the formation of quantum emitters. We investigate the relationship between the position of the emitters—determined via spectroscopy and photoluminescence measurements—and the location of threading dislocations—characterized both via atomic force microscopy and cathodoluminescence. We find that quantum emitters do not correlate with stacking faults or dislocations instead, they are more likely to originate from point defects or impurities whose density is modulated by the local extended defect density.
Publisher: Bentham Science Publishers Ltd.
Date: 2007
Publisher: Elsevier BV
Date: 2005
DOI: 10.1016/J.DCI.2005.03.003
Abstract: IMGT, the international ImMunoGeneTics information system (imgt.cines.fr) provides a common access to expertly annotated data on the genome, proteome, genetics and structure of immunoglobulins (IG), T cell receptors (TR), major histocompatibility complex (MHC), and related proteins of the immune system (RPI) of human and other vertebrates. The NUMEROTATION concept of IMGT-ONTOLOGY has allowed to define a unique numbering for the variable domains (V-DOMAINs) and constant domains (C-DOMAINs) of the IG and TR, which has been extended to the V-LIKE-DOMAINs and C-LIKE-DOMAINs of the immunoglobulin superfamily (IgSF) proteins other than the IG and TR (Dev Comp Immunol 27:55--77, 2003 29:185--203, 2005). In this paper, we describe the IMGT unique numbering for the groove domains (G-DOMAINs) of the MHC and for the G-LIKE-DOMAINs of the MHC superfamily (MhcSF) proteins other than MHC. This IMGT unique numbering leads, for the first time, to the standardized description of the mutations, allelic polymorphisms, two-dimensional (2D) representations and three-dimensional (3D) structures of the G-DOMAINs and G-LIKE-DOMAINs in any species, and therefore, is highly valuable for their comparative, structural, functional and evolutionary studies.
Publisher: Oxford University Press (OUP)
Date: 29-10-2011
DOI: 10.1093/NAR/GKQ1058
Publisher: Frontiers Media SA
Date: 31-05-2019
Publisher: Oxford University Press (OUP)
Date: 2004
DOI: 10.1093/NAR/GKH015
Publisher: Wiley
Date: 18-08-2017
Publisher: Oxford University Press (OUP)
Date: 17-12-2005
DOI: 10.1093/NAR/GKI065
Publisher: MDPI AG
Date: 25-02-2023
DOI: 10.3390/MD21030154
Abstract: The venom of marine cone snails is mainly composed of peptide toxins called conopeptides, among which conotoxins represent those that are disulfide-rich. Publications on conopeptides frequently state that conopeptides attract considerable interest for their potent and selective activity, but there has been no analysis yet that formally quantifies the popularity of the field. We fill this gap here by providing a bibliometric analysis of the literature on cone snail toxins from 2000 to 2022. Our analysis of 3028 research articles and 393 reviews revealed that research in the conopeptide field is indeed prolific, with an average of 130 research articles per year. The data show that the research is typically carried out collaboratively and worldwide, and that discoveries are truly a community-based effort. An analysis of the keywords provided with each article revealed research trends, their evolution over the studied period, and important milestones. The most employed keywords are related to pharmacology and medicinal chemistry. In 2004, the trend in keywords changed, with the pivotal event of that year being the approval by the FDA of the first peptide toxin drug, ziconotide, a conopeptide, for the treatment of intractable pain. The corresponding research article is among the top ten most cited articles in the conopeptide literature. From the time of that article, medicinal chemistry aiming at engineering conopeptides to treat neuropathic pain r ed up, as seen by an increased focus on topological modifications (e.g., cyclization), electrophysiology, and structural biology.
Publisher: Elsevier BV
Date: 02-2013
Publisher: Wiley
Date: 2010
DOI: 10.1002/BIP.21400
Abstract: In recent years, the discovery of a large family of macrocyclic peptides, the cyclotides, has revealed Natures ingenuity in molecular drug design. The incorporation of a cyclic peptide backbone and a knotted arrangement of disulfide bridges into their structures confers extraordinary chemical, thermal, and enzymatic stability on these biologically active peptides. However, these structural attributes present challenges in the identification of cyclotides. Until now, the sequencing of cyclotides has been slow and inefficient owing to inherent difficulties in the separation of these hydrophobic peptides from plants, the multiple chemical and enzymatic derivatization steps required to make them amenable to mass spectrometric sequencing, and the lack of software tools to efficiently deal with these circular permutants. The current bottleneck slowing the speed of cyclotide sequencing is the requirement for multiple HPLC purification steps before analysis. Here, we have applied proteomic strategies to fast-track the discovery of known, modified and novel sequences. Using four fractions from a previously well-characterized cyclotide-containing plant species, Viola odorata, 11 new sequences, as well as a plethora of known and modified cyclotides, were uncovered. In addition, the methodology was validated through analysis of crude leaf extracts ofOldenlandia affinis and Arabidopsis thaliana. The unambiguous identification of a suite of cyclotides in the Oldenlandia affinis extract provided the ultimate proof-of-concept for this application. Major advances in methodology include the use of optimized LC-MS/MS conditions and design of a custom-built cyclotide database, in which mature cyclotide sequences are excised, replicated and appended, marking a new "era" for cyclotide sequencing.
Publisher: Oxford University Press (OUP)
Date: 06-11-2015
Abstract: Cyclic proteins have evolved for millions of years across all kingdoms of life to confer structural stability over their acyclic counterparts while maintaining intrinsic functional properties. Here, we show that cyclic miniproteins (or peptides) from Momordica (Cucurbitaceae) seeds evolved in species that erged from an African ancestor around 19 Ma. The ability to achieve head-to-tail cyclization of Momordica cyclic peptides appears to have been acquired through a series of mutations in their acyclic precursor coding sequences following recent and independent gene expansion event(s). Evolutionary analysis of Momordica cyclic peptides reveals sites that are under selection, highlighting residues that are presumably constrained for maintaining their function as potent trypsin inhibitors. Molecular dynamics of Momordica cyclic peptides in complex with trypsin reveals site-specific residues involved in target binding. In a broader context, this study provides a basis for selecting Momordica species to further investigate the biosynthesis of the cyclic peptides and for constructing libraries that may be screened against evolutionarily related serine proteases implicated in human diseases.
Publisher: Elsevier BV
Date: 10-2017
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.JMGM.2017.04.004
Abstract: c-Met is a transmembrane receptor tyrosine kinase and an important therapeutic target for anticancer drugs. In the present study, we systematically investigated the influence of a range of parameters on the correlation between experimental and calculated binding free energies of type II c-Met inhibitors. We especially focused on evaluating the impact of different force fields, binding energy calculation methods, docking protocols, conformation s ling strategies, and conformations of the binding site captured in several crystallographic structures. Our results suggest that the force fields, the protein flexibility, and the selected conformation of the binding site substantially influence the correlation coefficient, while the s ling strategies and ensemble docking only mildly affect the prediction accuracy. Structure-activity relationship study suggests that the structural determinants to the high binding affinity of the type II inhibitors originate from its overall linear shape, hydrophobicity, and two conserved hydrogen bonds. Results from this study will form the basis for establishing an efficient computational docking approach for c-Met type II inhibitors design.
Publisher: Oxford University Press (OUP)
Date: 2004
DOI: 10.1093/NAR/GKH042
Publisher: Springer New York
Date: 2008
Publisher: Elsevier BV
Date: 08-2020
Publisher: American Chemical Society (ACS)
Date: 21-10-2019
DOI: 10.1021/ACS.CHEMREV.9B00207
Abstract: The venom of the marine predatory cone snails (genus
Publisher: American Chemical Society (ACS)
Date: 25-09-2018
DOI: 10.1021/ACS.JMEDCHEM.8B00967
Abstract: The α3β4 nicotinic acetylcholine receptor (nAChR) is an important target implicated in various disease states. α-Conotoxin TxID (1) is the most potent antagonist of α3β4 nAChR, but it also exhibits inhibition of α6/α3β4 nAChR. The results of alanine scanning of 1 suggested a vital role for Ser9 in the selectivity of the peptide. In this study, Ser9 was substituted with a series of 14 amino acids, including some non-natural amino acids, displaying different physicochemical characteristics to further improve the selectivity of 1 toward α3β4 nAChR. The pharmacological activities of the mutants were evaluated using an electrophysiological approach. The best selectivity was obtained with [S9K]TxID, 12, which inhibited α3β4 nAChR with an IC
Publisher: Springer Science and Business Media LLC
Date: 28-06-2013
Publisher: Bentham Science Publishers Ltd.
Date: 12-2011
DOI: 10.2174/138161211798999401
Abstract: The peptides present in the venoms of marine snails are used by the snails to capture prey, but they have also attracted the interest of drug designers because of their potent activity against therapeutically important targets. These peptides are typically disulfiderich and target a wide range of ion channels, transporters and receptors with exquisite selectivity. In this article, we discuss structural and biological studies on several classes of conotoxins that have potential as drug leads for the treatment of pain. The chemical re-engineering of conotoxins via cyclization has been particularly valuable in improving their biopharmaceutical properties. An excellent ex le is the α-conotoxin Vc1.1, for which several cyclized analogs have been made. One of them was shown to be orally active in a rat pain model and this analog is currently undergoing pre-clinical development for the treatment of neuropathic pain. Several other α-conotoxins, including ImI, AuIB and MII, have proved amenable to cyclization and in all cases improvements in stability are obtained upon cyclization, suggesting that cyclization is a generally applicable approach to conotoxin stabilization. A variety of other chemical re-engineering approaches have also been used. Minor re-engineering of χ-conotoxin MrIa to convert its N-terminal residue to pyroglutamic acid proved particularly successful and the modified derivative, Xen2174, is currently in clinical trials for neuropathic pain.
Publisher: Elsevier BV
Date: 07-2010
DOI: 10.1016/J.TOXICON.2010.03.002
Abstract: Cone snails are carnivorous marine gastropods that have evolved potent venoms to capture their prey. These venoms comprise a rich and erse cocktail of peptide toxins, or conopeptides, whose high ersity has arisen from an efficient hypermutation mechanism, combined with a high frequency of post-translational modifications. Conopeptides bind with high specificity to distinct membrane receptors, ion channels, and transporters of the central and muscular nervous system. As well as serving their natural function in prey capture, conopeptides have been utilized as versatile tools in neuroscience and have proven valuable as drug leads that target the nervous system in humans. This paper examines current knowledge on conopeptide sequences based on an analysis of gene and peptide sequences in ConoServer (www.conoserver.org), a specialized database of conopeptide sequences and three-dimensional structures. We describe updates to the content and organization of ConoServer and discuss correlations between gene superfamilies, cysteine frameworks, pharmacological families targeted by conopeptides, and the phylogeny, habitat, and diet of cone snails. The study identifies gaps in current knowledge of conopeptides and points to potential directions for future research.
Publisher: Springer Science and Business Media LLC
Date: 03-02-2020
Publisher: Wiley
Date: 13-02-2018
DOI: 10.1111/BPH.14115
Publisher: American Chemical Society (ACS)
Date: 10-11-2004
DOI: 10.1021/BI049098A
Abstract: Previous structural studies on the [Lys((-2))-Arg((-1))]endothelin-1 peptide (KR-ET-1), 540-fold less potent than ET-1, strongly suggested the presence of an intramolecular Arg(-1)-Asp(8) (R(-1)-D(8)) salt bridge that was also observed in the shorter [Lys((-2))-Arg((-1))-des(17-21)]endothelin-1 derivative (KR-CSH-ET). In addition, for these two analogues, we have shown that the Lys-Arg dipeptide, which belongs to the prosequence, significantly improves the formation of the native disulfide bonds (>or=96% instead of approximately 70% for ET-1). In contrast to what was inferred from NMR data, molecular dynamics simulations suggested that such an intramolecular salt bridge would be unstable. The KR-CSH-ET peptide has now been crystallized at pH 5.0 and its high-resolution structure determined ab initio at 1.13 A using direct methods. Unexpectedly, KR-CSH-ET was shown to be a head-to-tail symmetric dimer, and the overall interface involves two intermolecular R(-1)-D(8) salt bridges, a two-stranded antiparallel beta-sheet, and hydrophobic contacts. Molecular dynamics simulations carried out on this dimer clearly showed that the two intermolecular salt bridges were in this case very stable. Sedimentation equilibrium experiments unambiguously confirmed that KR-ET-1 and KR-CSH-ET also exist as dimers in solution at pH 5.0. On the basis of the new dimeric structure, previous NMR data were reinterpreted. Structure calculations were performed using 484 intramolecular and 38 intermolecular NMR-derived constraints. The solution and the X-ray structures of the dimer are very similar (mean rmsd of 0.85 A). Since the KR dipeptide at the N-terminus of KR-CSH-ET is present in the prosequence, it can be hypothesized that similar intermolecular salt bridges could be involved in the in vivo formation of the native disulfide bonds of ET-1. Therefore, it appears to be likely that the prosequence does assist the ET-1 folding in a chaperone-like manner before successive cleavages that yield the bioactive ET-1 hormone.
Publisher: Oxford University Press (OUP)
Date: 2015
Publisher: Wiley
Date: 07-2016
Publisher: American Chemical Society (ACS)
Date: 29-04-2013
DOI: 10.1021/JM400041H
Abstract: α-Conotoxin Vc1.1 specifically and potently inhibits the nicotinic acetylcholine receptor subtype α9α10 (α9α10 nAChR) and is a potential novel treatment for neuropathic pain. Here, we used a combination of computational modeling and electrophysiology experiments to determine the Vc1.1 binding site on the α9α10 nAChR. Interactions of Vc1.1 with two probable binding sites, α9α10 and α10α9, were modeled. Mutational energies calculated by assuming specific interactions in the α10α9 binding site correlated better with electrophysiological recordings than those assuming interactions with the α9α10 binding site. Two novel Vc1.1 analogues, [N9F]Vc1.1 and [N9W]Vc1.1, were predicted to have large differences in affinity between the two binding sites. Data from functional studies were consistent with computational predictions that assumed preferred binding of Vc1.1 to the α10α9 pocket. Moreover, our modeling study suggested that a single hydrogen bond formed between Vc1.1 and position 59 of the α10α9 pocket confers specificity to rat versus human α9α10 nAChRs.
Publisher: American Chemical Society (ACS)
Date: 25-03-2021
Publisher: American Chemical Society (ACS)
Date: 31-03-2018
Publisher: Springer Science and Business Media LLC
Date: 18-12-2015
DOI: 10.1038/NCOMMS10199
Abstract: Cyclotides are erse plant backbone cyclized peptides that have attracted interest as pharmaceutical scaffolds, but fundamentals of their biosynthetic origin remain elusive. Backbone cyclization is a key enzyme-mediated step of cyclotide biosynthesis and confers a measure of stability on the resultant cyclotide. Furthermore, cyclization would be desirable for engineered peptides. Here we report the identification of four asparaginyl endopeptidases (AEPs), proteases implicated in cyclization, from the cyclotide-producing plant Oldenlandia affinis. We recombinantly express Oa AEP1 b and find it functions preferably as a cyclase by coupling C-terminal cleavage of propeptide substrates with backbone cyclization. Interestingly, Oa AEP1 b cannot cleave at the N-terminal site of O. affinis cyclotide precursors, implicating additional proteases in cyclotide biosynthesis. Finally, we demonstrate the broad utility of this enzyme by cyclization of peptides unrelated to cyclotides. We propose that recombinant Oa AEP1 b is a powerful tool for use in peptide engineering applications where increased stability of peptide products is desired.
Publisher: American Chemical Society (ACS)
Date: 27-04-2021
Publisher: Elsevier BV
Date: 12-2017
Publisher: American Chemical Society (ACS)
Date: 19-02-2018
Abstract: Several cyclic peptides have been reported to have unexpectedly high membrane permeability. Of these, cyclosporin A is perhaps the most well-known ex le, particularly in light of its relatively high molecular weight. Observations that cyclosporin A changes conformation depending on its solvent environment led to the hypothesis that conformational dynamics is a prerequisite for its permeability however, this hypothesis has been difficult to validate experimentally. Here, we use molecular dynamics simulations to explicitly determine the conformational behavior of cyclosporin A and other related cyclic peptides as they spontaneously transition between different environments, including through a lipid bilayer. These simulations are referenced against simulations in explicit water, chloroform, and cyclohexane and further validated against NMR experiments, measuring conformational exchange, nuclear spin relaxation, and three-dimensional structures in membrane-mimicking environments, such as in dodecylphosphocholine micelles, to build a comprehensive understanding of the role of dynamics. We find that conformational flexibility is a key determinant of the membrane permeability of cyclosporin A and similar membrane-permeable cyclic peptides, as conformationally constrained variants have limited movement into, then through, and finally out of the membrane in silico. We envisage that a better understanding of dynamics might thus provide new opportunities to modulate peptide function and enhance their delivery.
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.NEUROPHARM.2017.07.036
Abstract: The active components of animal venoms are mostly peptide toxins, which typically target ion channels and receptors of both the central and peripheral nervous system, interfering with action potential conduction and/or synaptic transmission. The high degree of sequence conservation of their molecular targets makes a range of these toxins active at human receptors. The high selectivity and potency displayed by some of these toxins have prompted their use as pharmacological tools as well as drugs or drug leads. Molecular modelling has played an essential role in increasing our molecular-level understanding of the activity and specificity of animal toxins, as well as engineering them for biotechnological and pharmaceutical applications. This review focuses on the biological insights gained from computational and experimental studies of animal venom toxins interacting with membranes and ion channels. A host of recent X-ray crystallography and electron-microscopy structures of the toxin targets has contributed to a dramatic increase in the accuracy of the molecular models of toxin binding modes greatly advancing this exciting field of study. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.'
Publisher: Elsevier BV
Date: 05-2013
Publisher: Proceedings of the National Academy of Sciences
Date: 13-07-2015
Abstract: The α9α10 nicotinic AChR (nAChR) subtype is a recently identified target for the development of breast cancer chemotherapeutics and analgesics, particularly to treat neuropathic pain. Structure/function analyses of antagonists of this subtype are therefore essential for the development of specific therapeutic compounds. The Conus genus is a rich source of pharmacologically active peptides, and we report here that the αO-conotoxin GeXIVA is a potent and selective antagonist of the α9α10 nAChR subtype. GeXIVA displays unique structural properties among other Conus peptides and represents a previously unidentified template for molecules active against neuropathic pain.
Publisher: American Chemical Society (ACS)
Date: 15-09-2015
DOI: 10.1021/ACSCHEMBIO.5B00454
Abstract: Cyclotides are macrocyclic proteins produced by plants for host defense. Although they occur sparsely in other plant families, cyclotides have been detected in every Violaceae plant species so far screened. Many of the Violaceae species examined until now have been from closely related geographical regions or habitats. To test the hypothesis that cyclotides are ubiquitous in this family, two geographically isolated (and critically endangered) species of Australasian Violaceae, namely Melicytus chathamicus and M. latifolius, were examined. Surprisingly, we discovered a suite of cyclotides possessing novel sequence features, including a lysine-rich nature, distinguishing them from "conventional" cyclotides and suggesting that they might have different physiological activities in plants to those reported to date. The newly discovered cyclotides were found to bind to lipid membranes and were cytotoxic against cancer cell lines but had low toxicity against red blood cells, which is advantageous for potential therapeutic applications. This suite of novel Lys-rich cyclotides emphasizes the broad ersity of cyclotides in Violaceae species.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0MD00173B
Abstract: Marine cone snails produce an array of hormone-like peptides in their venom, providing bioactive leads for developing peptide drugs and small molecule mimetics.
Publisher: Springer Science and Business Media LLC
Date: 27-03-2020
DOI: 10.1038/S41467-020-15418-2
Abstract: Asparaginyl endopeptidases (AEPs) catalyze the key backbone cyclization step during the biosynthesis of plant-derived cyclic peptides. Here, we report the identification of two AEPs from Momordica cochinchinensis and biochemically characterize MCoAEP2 that catalyzes the maturation of trypsin inhibitor cyclotides. Recombinantly produced MCoAEP2 catalyzes the backbone cyclization of a linear cyclotide precursor (MCoTI-II-NAL) with a k cat /K m of 620 mM −1 s −1 , making it one of the fastest cyclases reported to date. We show that MCoAEP2 can mediate both the N-terminal excision and C-terminal cyclization of cyclotide precursors in vitro. The rate of cyclization/hydrolysis is primarily influenced by varying pH, which could potentially control the succession of AEP-mediated processing events in vivo. Furthermore, MCoAEP2 efficiently catalyzes the backbone cyclization of an engineered MCoTI-II analog with anti-angiogenic activity. MCoAEP2 provides enhanced synthetic access to structures previously inaccessible by direct chemistry approaches and enables the wider application of trypsin inhibitor cyclotides in biotechnology applications.
Publisher: American Chemical Society (ACS)
Date: 31-01-2020
DOI: 10.1021/ACS.JMEDCHEM.9B01563
Abstract: Tachyplesin I (TPI) is a cationic β-hairpin antimicrobial peptide with broad-spectrum, potent antimicrobial activity. In this study, the all d-amino acid analogue of TPI (TPAD) was synthesized, and its structure and activity were determined. TPAD has comparable antibacterial activity to TPI on 14 bacterial strains, including four drug-resistant bacteria. Importantly, TPAD has significantly improved stability against enzymatic degradation and decreased hemolytic activity compared to TPI, indicating that it has better therapeutic potential. The induction of bacterial resistance using low concentrations of TPAD resulted in the activation of the QseC/B two-component system. Deletion of this system resulted in at least five-fold improvement of TPAD activity, and the combined use of TPAD with LED209, a QseC/B inhibitor, significantly enhanced the bactericidal effect against three classes of multidrug-resistant bacteria.
Publisher: Elsevier BV
Date: 2014
DOI: 10.1016/J.BBAPAP.2013.05.002
Abstract: Cyclic proteins (CPs) have circular chains with a continuous cycle of peptide bonds. Their unique structural traits result in greater stability and resistance to degradation when compared to their acyclic counterparts. They are also promising targets for pharmaceutical/therapeutic applications. To date, only a few hundred CPs are known, although recent studies suggest that their numbers might be substantially higher. Here we developed a first-of-its-kind, accurate and high-throughput method called CyPred that predicts whether a given protein chain is cyclic. CyPred considers currently well-represented CP families: cyclotides, cyclic defensins, bacteriocins, and trypsin inhibitors. Empirical tests demonstrate that CyPred outperforms commonly used alignment methods. We used CyPred to estimate the incidence of CPs and found ~3500 putative CPs among 5.7+ million chains from 642 fully sequenced proteomes from archaea, bacteria, and eukaryotes. The median number of putative CPs per species ranges from three for archaea proteomes to two for eukaryotes/bacteria, with 7% of archaea, 11% of bacterial, and 16% of eukaryotic proteomes having 10+ CPs. The differences in the estimated fractions of CPs per proteome are as large as three orders of magnitude. Among eukaryotes, animals have higher ratios of CPs compared to fungi, while plants have the largest spread of the ratios. We also show that proteomes enriched in cyclic proteins evolve more slowly than proteomes with fewer cyclic chains. Our results suggest that further research is needed to fully uncover the scope and potential of cyclic proteins. A list of putative CPs and the CyPred method are available at biomine.ece.ualberta.ca/CyPred/. This article is part of a Special Issue entitled: Computational Proteomics, Systems Biology & Clinical Implications. Guest Editor: Yudong Cai.
Publisher: MDPI AG
Date: 05-04-2018
DOI: 10.3390/MD16040118
Publisher: Springer Science and Business Media LLC
Date: 16-07-2014
Publisher: American Chemical Society (ACS)
Date: 27-09-2022
DOI: 10.1021/ACS.JMEDCHEM.2C00793
Abstract: In this work, cysteine staples were used as a late-stage functionalization strategy to ersify peptides and build conjugates targeting the melanocortin G-protein-coupled receptors [melanocortin receptor-1 (MC1R) and MC3R-MC5R]. Monocyclic and bicyclic agonists based on sunflower trypsin inhibitor-1 were used to generate a selection of stapled peptides that were evaluated for binding (p
Publisher: Elsevier BV
Date: 09-2009
Publisher: Oxford University Press (OUP)
Date: 22-01-2007
DOI: 10.1093/BFGP/ELM032
Abstract: The immunoglobulin superfamily (IgSF) comprises the immunoglobulins (IG), T cell receptors (TR) and proteins that have the common feature of having at least one Ig-like domain. The major histocompatibility complex (MHC) superfamily (MhcSF) comprises, in addition to the MHC, proteins which share the common feature of having Mhc-like domains. IMGT, the international ImMunoGeneTics information system (imgt.cines.fr) has set up a unique numbering system and standardized 2D graphical representations, or IMGT Colliers de Perles, which take into account the structural features of the Ig-like and Mhc-like domains. In this article, we review the IMGT Scientific chart rules for the description of the IgSF (V and C types) and of the MhcSF (G type) domains. These rules are based on the IMGT-ONTOLOGY axioms and concepts and are applicable for the sequence and structure analysis, whatever the species, the IgSF or MhcSF protein, or the chain type. These IMGT Colliers de Perles are particularly useful for antibody engineering, sequence-structure analysis, visualization and comparison of positions for mutations, polymorphisms and contact analysis.
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.BCP.2018.07.007
Abstract: The ribbon isomer of α-conotoxin AuIB has 10-fold greater potency than the wild-type globular isomer at inhibiting nicotinic acetylcholine receptors (nAChRs) in rat parasympathetic neurons, and unlike its globular isoform, ribbon AuIB only targets a specific stoichiometry of the α3β4 nAChR subtype. Previous electrophysiological recordings of AuIB indicated that ribbon AuIB binds to the α3(+)α3(-) interface within the nAChR extracellular domain, which is displayed by the (α3)
Publisher: Springer Science and Business Media LLC
Date: 14-09-2016
DOI: 10.1038/NATURE19791
Publisher: Frontiers Media SA
Date: 2013
Publisher: CABI
Date: 2010
DOI: 10.1079/9781845936570.0040
Abstract: is chapter provides an overview of plant antimicrobial peptides. It mainly focuses on one particular class of plant defence peptides, namely the cyclotides, which have been discovered over the last decade in plants from the Rubiaceae , Violaceae and Cucurbitaceae families. Cyclotides have a head-to-tail cyclized peptide backbone and a cystine knot motif formed from their six conserved cysteine residues, which makes them exceptionally stable. This chapter describes their isolation and characterization, structure and biosynthesis, and applications. The structural stability of cyclotides makes them excellent scaffolds for the engineering of novel therapeutic proteins. Advances in methods for the production of cyclotides and their potential clinical applications are also described.
Publisher: American Chemical Society (ACS)
Date: 10-04-2014
DOI: 10.1021/CR400401E
Publisher: Springer Science and Business Media LLC
Date: 2009
Publisher: American Chemical Society (ACS)
Date: 19-02-2020
Publisher: Elsevier BV
Date: 12-2013
Publisher: Oxford University Press (OUP)
Date: 03-11-2012
DOI: 10.1093/NAR/GKR886
Publisher: Wiley
Date: 18-09-2019
Abstract: Naturally occurring constrained peptides are frequently used as scaffolds for bioactive peptide grating due to their high stability. Here, we used in silico methods to design several constrained peptides comprising a scorpion toxin scaffold, a MDM2 binding epitope, and a cluster of positively charged residues. The designed peptides displayed varied binding affinity to MDM2 despite differing by only one or two residues. One of the peptides, SC426, had nanomolar binding affinity (K
Publisher: Elsevier BV
Date: 03-2013
DOI: 10.1016/J.PEPTIDES.2013.01.009
Abstract: Peptide de13a was previously purified from the venom of the worm-hunting cone snail Conus delessertii from the Yucatán Channel, México. This peptide has eight cysteine (Cys) residues in the unique arrangement C-C-C-CC-C-C-C, which defines the cysteine framework XIII ("-" represents one or more non-Cys residues). Remarkably, δ-hydroxy-lysine residues have been found only in conotoxin de13a, which also contains an unusually high proportion of hydroxylated amino acid residues. Here, we report the cDNA cloning of the complete precursor De13.1 of a related peptide, de13b, which has the same Cys framework and inter-Cys spacings as peptide de13a, and shares high protein/nucleic acid sequence identity (87%/90%) with de13a, suggesting that both peptides belong to the same conotoxin gene superfamily. Analysis of the signal peptide of precursor De13.1 reveals that this precursor belongs to a novel conotoxin gene superfamily that we chose to name gene superfamily G. Thus far superfamily G only includes two peptides, each of which contains the same, distinctive Cys framework and a high proportion of amino acid residues with hydroxylated side chains.
Publisher: Wiley
Date: 09-08-2016
DOI: 10.1002/BIT.25993
Publisher: Oxford University Press (OUP)
Date: 06-2001
DOI: 10.1093/BIOINFORMATICS/17.6.541
Abstract: Motivation: The prediction of the regions of homology models that can be ‘restrained by’ or ‘copied from’ the basis structures is a vital step in correct model generation, because these regions are the models most accurate part. However, there is no ideal method for the identification of their limits. In most algorithms their length depends on the number of family members and definitions of secondary structure. Results: The algorithm SCORE steps away from the conventional definitions of the core to identify from large numbers of basis structures those regions that can be considered structurally related to a target sequence. The use of \\batchmode \\documentclass[fleqn,10pt,legalpaper]{article} \\usepackage{amssymb} \\usepackage{amsfonts} \\usepackage{amsmath} \\pagestyle{empty} \\begin{document} \\({\\phi},\\ {\\psi}\\) \\end{document}constraints to accurately pinpoint the regions that are conserved across a family and environmentally constrained substitution tables to extend these regions allows SCORE to rapidly (generally in under 1 s, an order of magnitude faster than methods such as MODELLER) identify and build the core of homology models from the alignments of the target sequence to the basis structures. The SCORE algorithm was used to build 114 model cores. In only two cases was the core size less than 50% of the structure and all the cores built had an RMSD of 3.7 Âor less to the target structure. Availability: The algorithm is available upon request. Contact: charlotte@cryst.bioc.cam.ac.uk * To whom correspondence should be addressed.
Publisher: Wiley
Date: 09-2013
DOI: 10.1002/BIP.22258
Abstract: Cyclotides are a large family of plant peptides characterized by their cyclic cystine knot composed of a circular backbone and three disulfide bonds that impart exceptional stability. They, and several acyclic variants, have been isolated from plants within the Rubiaceae, Violaceae, Cucurbitaceae, Fabaceae, Solanaceae, and Poaceae families. A variety of chemical and genetic approaches have been applied for the discovery and characterization of cyclotides. As investigations of cyclotide expression, distribution, and phylogeny rapidly increase, the authors have proposed the inclusion of information pertaining to plant species that have been analyzed but do not appear to express cyclotides into the CyBase database. CyBase is dedicated to providing web tools and information about cyclic peptides and proteins to the scientific community. Including detailed information about s ling and analysis parameters of plant species that have been investigated but not published elsewhere should assist in the process of selecting species for establishing new cyclotide discovery projects, as well as for detailed reanalysis using alternative technical approaches. In summary, the collection and deposition of all plant species that have been examined (whether cyclotides have been found or not) would help to impart a deeper understanding of cyclotide discovery, evolution, and physiological function. © 2013 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 100: 433–437, 2013.
Publisher: Wiley
Date: 07-01-2014
DOI: 10.1096/FJ.13-244103
Publisher: Elsevier BV
Date: 04-2008
DOI: 10.1016/J.BIOCHI.2007.09.003
Abstract: IMGT, the international ImMunoGeneTics information system (imgt.cines.fr), is the reference in immunogenetics and immunoinformatics. IMGT standardizes and manages the complex immunogenetic data which include the immunoglobulins (IG) or antibodies, the T cell receptors (TR), the major histocompatibility complex (MHC) and the related proteins of the immune system (RPI) which belong to the immunoglobulin superfamily (IgSF) and the MHC superfamily (MhcSF). The accuracy and consistency of IMGT data and the coherence between the different IMGT components (databases, tools and Web resources) are based on IMGT-ONTOLOGY, the first ontology for immunogenetics and immunoinformatics. IMGT-ONTOLOGY manages the immunogenetics knowledge through erse facets relying on seven axioms, "IDENTIFICATION", "DESCRIPTION", "CLASSIFICATION", "NUMEROTATION", "LOCALIZATION", "ORIENTATION" and "OBTENTION", that postulate that objects, processes and relations have to be identified, described, classified, numerotated, localized, orientated, and that the way they are obtained has to be determined. These axioms constitute the Formal IMGT-ONTOLOGY, also designated as IMGT-Kaleidoscope. Through the ex le of the IG molecular synthesis, the concepts generated from the "IDENTIFICATION", "DESCRIPTION", "CLASSIFICATION" and "NUMEROTATION" axioms are detailed with their main instances and semantic relations. The axioms have been essential for the conceptualization of the molecular immunogenetics knowledge and can be used to generate concepts for multi scale approaches at the molecule, cell, tissue, organ, organism or population level, emphasizing the generalization of the application domain. In that way the Formal IMGT-ONTOLOGY represents a paradigm for the elaboration of ontologies in system biology.
Publisher: Springer Science and Business Media LLC
Date: 20-08-2015
DOI: 10.1038/SREP13264
Abstract: Cyclic α-conotoxin Vc1.1 (cVc1.1) is an orally active peptide with analgesic activity in rat models of neuropathic pain. It has two disulfide bonds, which can have three different connectivities, one of which is the native and active form. In this study we used computational modeling and nuclear magnetic resonance to design a disulfide-deleted mutant of cVc1.1, [C2H,C8F]cVc1.1, which has a larger hydrophobic core than cVc1.1 and, potentially, additional surface salt bridge interactions. The new variant, hcVc1.1, has similar structure and serum stability to cVc1.1 and is highly stable at a wide range of pH and temperatures. Remarkably, hcVc1.1 also has similar selectivity to cVc1.1, as it inhibited recombinant human α9α10 nicotinic acetylcholine receptor-mediated currents with an IC 50 of 13 μM and rat N-type (Ca v 2.2) and recombinant human Ca v 2.3 calcium channels via GABA B receptor activation, with an IC 50 of ~900 pM. Compared to cVc1.1, the potency of hcVc1.1 is reduced three-fold at both analgesic targets, whereas previous attempts to replace Vc1.1 disulfide bonds by non-reducible dicarba linkages resulted in at least 30-fold decreased activity. Because it has only one disulfide bond, hcVc1.1 is not subject to disulfide bond shuffling and does not form multiple isomers during peptide synthesis.
Publisher: Elsevier BV
Date: 2005
DOI: 10.1016/J.DCI.2004.07.003
Abstract: IMGT, the international ImMunoGeneTics information system (imgt.cines.fr) provides a common access to expertly annotated data on the genome, proteome, genetics and structure of immunoglobulins (IG), T cell receptors (TR), major histocompatibility complex (MHC), and related proteins of the immune system (RPI) of human and other vertebrates. The NUMEROTATION concept of IMGT-ONTOLOGY has allowed to define a unique numbering for the variable domains (V-DOMAINs) and for the V-LIKE-DOMAINs. In this paper, this standardized characterization is extended to the constant domains (C-DOMAINs), and to the C-LIKE-DOMAINs, leading, for the first time, to their standardized description of mutations, allelic polymorphisms, two-dimensional (2D) representations and tridimensional (3D) structures. The IMGT unique numbering is, therefore, highly valuable for the comparative, structural or evolutionary studies of the immunoglobulin superfamily (IgSF) domains, V-DOMAINs and C-DOMAINs of IG and TR in vertebrates, and V-LIKE-DOMAINs and C-LIKE-DOMAINs of proteins other than IG and TR, in any species.
Publisher: American Chemical Society (ACS)
Date: 07-2021
Publisher: Wiley
Date: 31-05-2019
Abstract: The insecticidal effects of ω-hexatoxin-Hv1a, κ-hexatoxin-Hv1c and ω/κ-hexatoxin-Hv1h are currently attributed to action at calcium and potassium channels. By characterizing the binding of these toxins to neuronal membranes, we show that they have more potent effects as positive allosteric modulators (PAMs) of insect nicotinic acetylcholine receptors (nAChRs), consistent with their neuroexcitatory toxicology. Alanine scanning analysis of ω-hexatoxin-Hv1a reveals a structure-activity relationship for binding that mirrors that for insecticidal activity. Spinosyn A does not compete with ω-hexatoxin-Hv-1a for binding, and we show that these two PAMs have distinct pharmacology of binding indicating that they act at different receptor populations. These toxins represent valuable tools for the characterization of insect nAChRs and for the development of more selective agrochemicals.
Publisher: Springer Science and Business Media LLC
Date: 20-06-2018
DOI: 10.1038/S41467-018-04669-9
Abstract: Asparaginyl endopeptidases (AEPs) are proteases that have crucial roles in plant defense and seed storage protein maturation. Select plant AEPs, however, do not function as proteases but as transpeptidases (ligases) catalyzing the intra-molecular ligation of peptide termini, which leads to peptide cyclization. These ligase-type AEPs have potential biotechnological applications ranging from in vitro peptide engineering to plant molecular farming, but the structural features enabling these enzymes to catalyze peptide ligation/cyclization rather than proteolysis are currently unknown. Here, we compare the sequences, structures, and functions of erse plant AEPs by combining molecular modeling, sequence space analysis, and functional testing in planta. We find that changes within the substrate-binding pocket and an adjacent loop, here named the “marker of ligase activity”, together play a key role for AEP ligase efficiency. Identification of these structural determinants may facilitate the discovery of more ligase-type AEPs and the engineering of AEPs with tailored catalytic properties.
Publisher: Springer Science and Business Media LLC
Date: 12-08-2015
DOI: 10.1038/SREP12974
Abstract: The constitutively active tyrosine kinase BCR-ABL is the underlying cause of chronic myeloid leukemia (CML). Current CML treatments rely on the long-term use of tyrosine kinase inhibitors (TKIs), which target the ATP binding site of BCR-ABL. Over the course of treatment, 20–30% of CML patients develop TKI resistance, which is commonly attributed to point mutations in the drug-binding region. We design a new class of peptide inhibitors that target the substrate-binding site of BCR-ABL by grafting sequences derived from abltide, the optimal substrate of Abl kinase, onto a cell-penetrating cyclotide MCoTI-II. Three grafted cyclotides show significant Abl kinase inhibition in vitro in the low micromolar range using a novel kinase inhibition assay. Our work also demonstrates that a reengineered MCoTI-II with abltide sequences grafted in both loop 1 and 6 inhibits the activity of [T315I]Abl in vitro , a mutant Abl kinase harboring the “gatekeeper” mutation which is notorious for being multidrug resistant. Results from serum stability and cell internalization studies confirm that the MCoTI-II scaffold provides enzymatic stability and cell-penetrating properties to the lead molecules. Taken together, our study highlights that reengineered cyclotides incorporating abltide-derived sequences are promising substrate-competitive inhibitors for Abl kinase and the T315I mutant.
Publisher: Elsevier BV
Date: 11-2020
Publisher: Elsevier BV
Date: 10-2018
Publisher: Elsevier BV
Date: 12-2007
DOI: 10.1016/J.CRITREVONC.2007.04.011
Abstract: Due to their exquisite specificity for a given epitope on the target antigen, recombinant monoclonal antibodies (rmAb) can deliver "targeted therapy" in oncology. This review focuses on the structural bases of "antigen specificity" to aid clinical researchers and pharmacologists in managing these new drugs. The fine structure of the Fv (Fragment variable) module (combination of VH and VL domains) from the five unconjugated antibodies currently approved for cancer treatment, namely rituximab, cetuximab, alemtuzumab, trastuzumab and bevacizumab, is presented and analysed. Co-crystal and functional studies are reviewed to define rmAb residues contributing to antigen binding site (paratope)-epitope interfaces. The genetic origin of these recombinant monoclonal antibodies, determined through the IMGT/3Dstructure-DB database and IMGT/V-QUEST (imgt.cines.fr), is presented, allowing the evaluation of homologies between antibodies and their closest germline human counterparts and hence their possible immunogenicity. Overall, the IMGT standards appear as a first and crucial step in the evaluation of recombinant antibodies.
Publisher: American Chemical Society (ACS)
Date: 18-05-2012
DOI: 10.1021/JP301352D
Abstract: α-Conotoxins potently and specifically inhibit isoforms of nicotinic acetylcholine receptors (nAChRs) and are used as molecular probes and as drugs or drug leads. Interactions occurring during binding and unbinding events are linked to binding kinetics, and knowledge of these interactions could help in the development of α-conotoxins as drugs. Here, the unbinding process for the prototypical α-conotoxin ImI/α7-nAChR system was investigated theoretically, and three exit routes were identified using random accelerated molecular dynamics simulations. The route involving the smallest conformation perturbation was further ided into three subpathways, which were studied using steered molecular dynamics simulations. Of the three subpathways, two had better experimental support and lower potential of mean force, indicating that they might be s led more frequently. Additionally, these subpathways were supported by previous experimental studies. Several pairwise interactions, including a cation-π interaction and charge and hydrogen bond interactions, were identified as potentially playing important roles in the unbinding event.
Publisher: American Chemical Society (ACS)
Date: 22-01-2023
Publisher: American Chemical Society (ACS)
Date: 17-08-2017
Publisher: Wiley
Date: 07-2016
Abstract: Conotoxins are disulfide‐rich peptides found in the venoms of marine snails of the genus Conus . They have attracted great attention from the pharmaceutical industry because of their potential uses as drug leads, but like most peptides, conotoxins are susceptible to proteolysis and typically are not orally bioavailable. Here we discuss approaches that have been used to stabilise conotoxins to improve their potential pharmaceutical use. Specifically, we focus on the use of backbone cyclisation to improve their stability in biological fluids. The Microreview provides an introduction to the various classes of conotoxins, including their frameworks (cysteine patterns) and a background on the receptors that they interact with, as well as an analysis of the binding interactions between conotoxins and their receptors.
Publisher: Oxford University Press (OUP)
Date: 23-12-2007
DOI: 10.1093/NAR/GKM939
Publisher: Elsevier BV
Date: 04-2015
Publisher: American Chemical Society (ACS)
Date: 02-2021
Publisher: American Chemical Society (ACS)
Date: 21-06-2017
Publisher: Proceedings of the National Academy of Sciences
Date: 12-05-2020
Abstract: Spiders are one of the most successful venomous animals, with more than 48,000 described species. Most spider venoms are dominated by cysteine-rich peptides with a erse range of pharmacological activities. Some spider venoms contain thousands of unique peptides, but little is known about the mechanisms used to generate such complex chemical arsenals. We used an integrated transcriptomic, proteomic, and structural biology approach to demonstrate that the lethal Australian funnel-web spider produces 33 superfamilies of venom peptides and proteins. Twenty-six of the 33 superfamilies are disulfide-rich peptides, and we show that 15 of these are knottins that contribute % of the venom proteome. NMR analyses revealed that most of these disulfide-rich peptides are structurally related and range in complexity from simple to highly elaborated knottin domains, as well as double-knot toxins, that likely evolved from a single ancestral toxin gene.
Publisher: Springer Science and Business Media LLC
Date: 06-08-2011
Publisher: MDPI AG
Date: 22-12-2017
Publisher: Wiley
Date: 2010
DOI: 10.1002/BIP.21424
Abstract: CyBase is a database dedicated to the study of the sequences and three-dimensional structures of ribosomally synthesized, backbone cyclized proteins, and their synthetic variants. This article describes CyBase data and tools that are useful in the analysis of circular proteins. Circular proteins have now been discovered in organisms from all kingdoms of life, and given the current rate of discovery they could soon number in the thousands. Presently CyBase manages 427 protein sequences, 106 nucleic acid sequences, and 49 protein three-dimensional structures from 44 different species. Circular proteins are grouped into distinct classes according to their origin and sequence similarities. These classes include trypsin inhibitors, bacterial proteins, mushroom toxins, cyclotides, and cyclic defensins from primates. Several protein classification types are used in CyBase to designate proteins extracted from natural resources (wild type and precursor) or engineered (modified wild type, grafted, mutant, cyclic permutant, and acyclic permutant). CyBase has tools for the analysis of mass spectrum fingerprints of cyclic peptides, and assists in the discovery of new circular proteins. Some of the developments detailed here have been made specifically for the largest class of circular proteins, the cyclotides, but could be adapted for other classes of cyclic proteins. The cyclotide-specific tools include two-dimensional representations of domains and alternative displays of alignments for precursor sequences. This alignment prompted us to propose a revision of the cydclotide precursor organization, in which the repeated regions now include a small C-terminal region, which appears to have a significant role in the biosynthesis of mature cyclotides.
Publisher: Springer Science and Business Media LLC
Date: 25-07-2019
DOI: 10.1038/S41598-019-47273-7
Abstract: Asparaginyl endopeptidases (AEPs) are a class of enzymes commonly associated with proteolysis in the maturation of seed storage proteins. However, a subset of AEPs work preferentially as peptide ligases, coupling release of a leaving group to formation of a new peptide bond. These “ligase-type” AEPs require only short recognition motifs to ligate a range of targets, making them useful tools in peptide and protein engineering for cyclisation of peptides or ligation of separate peptides into larger products. Here we report the recombinant expression, ligase activity and cyclisation kinetics of three new AEPs from the cyclotide producing plant Oldenlandia affinis with superior kinetics to the prototypical recombinant AEP ligase OaAEP1 b . These AEPs work preferentially as ligases at both acidic and neutral pH and we term them “canonical AEP ligases” to distinguish them from other AEPs where activity preferences shift according to pH. We show that these ligases intrinsically favour ligation over hydrolysis, are highly efficient at cyclising two unrelated peptides and are compatible with organic co-solvents. Finally, we demonstrate the broad scope of recombinant AEPs in biotechnology by the backbone cyclisation of an intrinsically disordered protein, the 25 kDa malarial vaccine candidate Plasmodium falciparum merozoite surface protein 2 (MSP2).
Start Date: 2007
End Date: 2009
Funder: Australian Research Council
View Funded ActivityStart Date: 2021
End Date: 2023
Funder: Australian Research Council
View Funded ActivityStart Date: 2015
End Date: 2019
Funder: Australian Research Council
View Funded ActivityStart Date: 2015
End Date: 06-2021
Amount: $634,100.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2007
End Date: 12-2010
Amount: $266,090.00
Funder: Australian Research Council
View Funded ActivityStart Date: 09-2021
End Date: 09-2024
Amount: $417,000.00
Funder: Australian Research Council
View Funded Activity