ORCID Profile
0000-0001-9520-6623
Current Organisations
Garvan Institute of Medical Research
,
CSIRO (Data61)
,
University of New South Wales
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Publisher: IEEE
Date: 09-2015
Publisher: Proceedings of the National Academy of Sciences
Date: 17-11-2015
Abstract: A key remaining frontier in our understanding of biological systems is the “dark proteome”—that is, the regions of proteins where molecular conformation is completely unknown. We systematically surveyed these regions, finding that nearly half of the proteome in eukaryotes is dark and that, surprisingly, most of the darkness cannot be accounted for. We also found that the dark proteome has unexpected features, including an association with secretory tissues, disulfide bonding, low evolutionary conservation, and very few known interactions with other proteins. This work will help future research shed light on the remaining dark proteome, thus revealing molecular processes of life that are currently unknown.
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.STR.2019.09.001
Abstract: Visualization of molecular structures is one of the most common tasks carried out by structural biologists, typically using software, such as Chimera, COOT, PyMOL, or VMD. In this Perspective article, we outline how past developments in computer graphics and data visualization have expanded the understanding of biomolecular function, and we summarize recent advances that promise to further transform structural biology. We also highlight how progress in molecular graphics has been impeded by communication barriers between two communities: the computer scientists driving these advances, and the structural and computational biologists who stand to benefit. By pointing to canonical papers and explaining technical progress underlying new graphical developments in simple terms, we aim to improve communication between these communities this, in turn, would help shape future developments in molecular graphics.
Publisher: Springer Science and Business Media LLC
Date: 29-01-2015
DOI: 10.1038/NMETH.3258
Publisher: Springer Science and Business Media LLC
Date: 28-11-2008
Abstract: Complexity is a key problem when visualizing biological networks as the number of entities increases, most graphical views become incomprehensible. Our goal is to enable many thousands of entities to be visualized meaningfully and with high performance. We present a new visualization tool, Arena3D, which introduces a new concept of staggered layers in 3D space. Related data – such as proteins, chemicals, or pathways – can be grouped onto separate layers and arranged via layout algorithms, such as Fruchterman-Reingold, distance geometry, and a novel hierarchical layout. Data on a layer can be clustered via k-means, affinity propagation, Markov clustering, neighbor joining, tree clustering, or UPGMA ('unweighted pair-group method with arithmetic mean'). A simple input format defines the name and URL for each node, and defines connections or similarity scores between pairs of nodes. The use of Arena3D is illustrated with datasets related to Huntington's disease. Arena3D is a user friendly visualization tool that is able to visualize biological or any other network in 3D space. It is free for academic use and runs on any platform. It can be downloaded or lunched directly from arena3d.org . Java3D library and Java 1.5 need to be pre-installed for the software to run.
Publisher: Springer Science and Business Media LLC
Date: 03-2010
DOI: 10.1038/NMETH.1436
Abstract: High-throughput studies of biological systems are rapidly accumulating a wealth of 'omics'-scale data. Visualization is a key aspect of both the analysis and understanding of these data, and users now have many visualization methods and tools to choose from. The challenge is to create clear, meaningful and integrated visualizations that give biological insight, without being overwhelmed by the intrinsic complexity of the data. In this review, we discuss how visualization tools are being used to help interpret protein interaction, gene expression and metabolic profile data, and we highlight emerging new directions.
Publisher: Springer US
Date: 1995
Publisher: Wiley
Date: 06-2016
DOI: 10.1111/CGF.12894
Publisher: Elsevier BV
Date: 06-2017
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 02-2022
Publisher: Oxford University Press (OUP)
Date: 1988
DOI: 10.1093/JXB/39.6.763
Publisher: Elsevier BV
Date: 08-2019
Publisher: Springer Science and Business Media LLC
Date: 03-2010
DOI: 10.1038/NMETH.F.301
Abstract: Methods and tools for visualizing biological data have improved considerably over the last decades, but they are still inadequate for some high-throughput data sets. For most users, a key challenge is to benefit from the deluge of data without being overwhelmed by it. This challenge is still largely unfulfilled and will require the development of truly integrated and highly useable tools.
Publisher: IEEE
Date: 11-2016
Publisher: Elsevier BV
Date: 06-1997
Abstract: We have used a novel, largely automated, calculation method to refine the NMR solution structure of the pleckstrin homology domain of beta-spectrin. The method is called ARIA for Ambiguous Restraints for Iterative Assignment. The starting point for ARIA is an almost complete assignment of the proton chemical shifts, and a list of partially assigned NOEs, mostly sequential and secondary structure NOEs. The restraint list is then augmented by automatically interpreting peak lists generated by automated peak-picking. The central task of ARIA is the assignment of ambiguous NOEs during the structure calculation using a combination of ambiguous distance restraints and an iterative assignment strategy. In addition, ARIA calibrates ambiguous NOEs to derive distance restraints, merges overlapping data sets to remove duplicate information, and uses empirical rules to identify erroneous peaks. While the distance restraints for the structure calculations were exclusively extracted from homonuclear 2D experiments, ARIA is especially suited for the analysis of multidimensional spectra. Applied to the pleckstrin homology domain, ARIA generated structures of good quality, and of sufficiently high accuracy to solve the X-ray crystal structure of the same domain by molecular replacement. The comparison of the free NMR solution structure to the X-ray structure, which is complexed to D-myo-inositol-1,4,5-triphosphate, shows that the ligand primarily induces a disorder-order transition in the binding loops, which are disordered in the NMR ensemble but well ordered in the crystal. The structural core of the protein is unaffected, as evidenced by a backbone root-mean-square difference between the average NMR coordinates and the X-ray crystal structure for the secondary structure elements of less than 0.6 A.
Publisher: Cold Spring Harbor Laboratory
Date: 11-09-2021
DOI: 10.1101/2021.09.10.459756
Abstract: Variant analysis is a core task in bioinformatics that requires integrating data from many sources. This process can be helped by using 3D structures of proteins, which can provide a spatial context that can provide insight into how variants affect function. Many available tools can help with mapping variants onto structures but each has specific restrictions, with the result that many researchers fail to benefit from valuable insights that could be gained from structural data. To address this, we have created a streamlined system for incorporating 3D structures into variant analysis. Variants can be easily specified via URLs that are easily readable and writable, and use the notation recommended by the Human Genome Variation Society (HGVS). For ex le, ‘ aquaria.app/SARS-CoV-2/S/?N501Y ’ specifies the N501Y variant of SARS-CoV-2 S protein. In addition to mapping variants onto structures, our system provides summary information from multiple external resources, including COSMIC, CATH-FunVar, and PredictProtein. Furthermore, our system identifies and summarizes structures containing the variant, as well as the variant-position. Our system supports essentially any mutation for any well-studied protein, and uses all available structural data — including models inferred via very remote homology — integrated into a system that is fast and simple to use. By giving researchers easy, streamlined access to a wealth of structural information during variant analysis, our system will help in revealing novel insights into the molecular mechanisms underlying protein function in health and disease. Our resource is freely available at the project home page ( aquaria.app ). After peer review, the code will be openly available via a GPL version 2 license at github.com/ODonoghueLab/Aquaria . PSSH2, the database of sequence-to-structure alignments, is also freely available for download at ecord/4279164 . sean@odonoghuelab.org None.
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C3FD00138E
Abstract: Intrinsically disordered regions (IDRs) in proteins are still not well understood, but are increasingly recognised as important in key biological functions, as well as in diseases. IDRs often confound experimental structure determination—however, they are present in many of the available 3D structures, where they exhibit a wide range of conformations, from ill-defined and highly flexible to well-defined upon binding to partner molecules, or upon post-translational modifications. Analysing such large conformational variations across ensembles of 3D structures can be complex and difficult our goal in this paper is to improve this situation by augmenting traditional approaches (molecular graphics and principal components) with methods from human–computer interaction and information visualisation, especially parallel coordinates. We present a new tool integrating these approaches, and demonstrate how it can dissect ensembles to reveal functional insights into conformational variation and intrinsic disorder.
Publisher: Oxford University Press (OUP)
Date: 1993
Abstract: Previous attempts to determine the solution structures of homodimeric 'leucine zippers' using nuclear magnetic resonance (NMR) spectroscopy have been impeded by the complete symmetry of these coiled-coil molecules, which makes it impossible a priori to distinguish between intra- and intermonomer dipolar connectivities. Consequently, a number of ad hoc approaches have been used in an attempt to derive tertiary solution structures of these molecules from the NMR data. In this paper we present a more rigorous approach for analysing the NMR spectra of symmetric coiled-coil proteins. This analysis is based on calculations of intra- and intermonomer interproton distances in the recently determined crystal structure of the GCN4 leucine zipper [O'Shea, E.K., Klemm, J.D., Kim, P.S. and Alber, T. (1991) Science, 254, 539-543] and in symmetric coiled-coil models of the leucine zippers of GCN4 and the human oncoprotein Jun which we constructed using a dynamic simulated annealing approach. This analysis has enabled the formulation of a set of rules for interpreting the NMR spectra of symmetric coiled-coil proteins and has also led to the prediction of novel dipolar connectivities which we demonstrate in a 2-D NMR spectrum of the homodimeric Jun leucine zipper.
Publisher: Elsevier BV
Date: 12-2018
Publisher: IEEE
Date: 11-2014
Publisher: Springer Science and Business Media LLC
Date: 2000
Abstract: Crystallographic and NMR studies of insulin have revealed a highly flexible molecule with a range of different aggregation and structural states the importance of these states for the function of the hormone is still unclear. To address this question, we have studied the solution structure of the insulin R6 symmetric hexamer using NMR spectroscopy. Structure determination of symmetric oligomers by NMR is complicated due to 'symmetry ambiguity' between intra- and intermonomer NOEs, and between different classes of intermonomer NOEs. Hence, to date, only two symmetric tetramers and one symmetric pentamer (VTB, B subunit of verotoxin) have been solved by NMR: there has been no other symmetric hexamer or higher-order oligomer. Recently, we reported a solution structure for R6 insulin hexamer. However, in that study, a crystal structure was used as a reference to resolve ambiguities caused by the threefold symmetry the same method was used in solving VTB. Here, we have successfully recalculated R6 insulin using the symmetry-ADR method, a computational strategy in which ambiguities are resolved using the NMR data alone. Thus the obtained structure is a refinement of the previous R6 solution structure. Correlated motions in the final structural ensemble were analysed using a recently developed principal component method this suggests the presence of two major conformational substates. The study demonstrates that the solution structure of higher-order symmetric oligomers can be determined unambiguously from NMR data alone, using the symmetry-ADR method. This success bodes well for future NMR studies of higher-order symmetric oligomers. The correlated motions observed in the structural ensemble suggest a new insight into the mechanism of phenol exchange and the T6 R6 transition of insulin in solution.
Publisher: Oxford University Press (OUP)
Date: 15-04-2004
DOI: 10.1093/BIOINFORMATICS/BTH260
Abstract: Summary: In this paper we present SRS 3D, a new service that allows users to easily and rapidly find all related structures for a given target sequence structures can then be viewed together with sequences, alignments and sequence features (currently from UniProt, InterPro and PDB). Extensive user feedback confirms that SRS 3D is intuitive and useful especially for those not expert in structures. Availability: An SRS 3D server is provided at srs3d.ebi.ac.uk/ Supplementary information: Complete documentation is available (click the ‘Help’ button after login). Product information can be found at www.lionbioscience.com/SRS3D roducts/srs/srs-3d
Publisher: Elsevier BV
Date: 07-2015
Publisher: ACM
Date: 15-10-2016
Publisher: Springer Science and Business Media LLC
Date: 03-2010
DOI: 10.1038/NMETH.1427
Publisher: American Chemical Society (ACS)
Date: 11-1992
DOI: 10.1021/BI00160A028
Abstract: Two-dimensional nuclear magnetic resonance (NMR) spectroscopy in combination with distance geometry (DG) and dynamical simulated annealing (DSA) calculations have been used to determine the tertiary solution structure of a synthetic 29-residue fragment of von Willebrand factor (vWF). This fragment (D514-E542) represents an adhesion site on vWF for its platelet receptor, the glycoprotein Ib-IX complex (GP Ib-IX). The NMR data yielded 109 interproton distance measurements and two chi 1 dihedral angle constraints for use in DG and DSA calculations. Most prominent in the calculated family of solution structures was an hipathic, right-handed alpha-helix in the C-terminal segment of the peptide. We propose that this highly structured region may be important for the specific molecular interaction of vWF with the GP Ib-IX complex.
Publisher: Wiley
Date: 11-2018
Abstract: Despite substantial and successful projects for structural genomics, many proteins remain for which neither experimental structures nor homology-based models are known for any part of the amino acid sequence. These have been called "dark proteins," in contrast to non-dark proteins, in which at least part of the sequence has a known or inferred structure. It has been hypothesized that non-dark proteins may be more abundantly expressed than dark proteins, which are known to have much fewer sequence relatives. Surprisingly, the opposite has been observed: human dark and non-dark proteins had quite similar levels of expression, in terms of both mRNA and protein abundance. Such high levels of expression strongly indicate that dark proteins-as a group-are important for cellular function. This is remarkable, given how carefully structural biologists have focused on proteins crucial for function, and highlights the important challenge posed by dark proteins in future research.
Publisher: American Society for Clinical Investigation
Date: 03-10-2022
DOI: 10.1172/JCI160929
Publisher: Springer Science and Business Media LLC
Date: 04-1992
DOI: 10.1007/BF01874150
Abstract: In order to assess the direct effects of cyclosporine A (CsA) and rapamycin on B cells, we utilized a two-segment culture system of highly purified B lymphocytes consisting of induction (activation) in the presence of the formalinized Staphylococcus aureus bacteria and IL-2, and differentiation, respectively, in the presence of various combinations of cytokines. Results show that rapamycin strongly inhibited production of both IgM and IgG measured at the end of the secondary culture supported by IL-2/IL-6, whereas CsA up-regulated the immunoglobulin production. The stimulatory effect of CsA was also observed when preactivated B cells were recultured in absence of any cytokines. These results show that rapamycin and CsA have clearly distinct effects on human B lymphocyte responses in vitro. Rapamycin is a more potent in vitro immunosuppressant of B lymphocytes than CsA. It is effective at significantly lower concentrations, and it does not stimulate either the proliferation or antibody production by preactivated B cells.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.JMB.2019.01.044
Abstract: The epiproteome describes the set of all post-translational modifications (PTMs) made to the proteins comprising a cell or organism. The extent of the epiproteome is still largely unknown however, advances in experimental techniques are beginning to produce a deluge of data, tracking dynamic changes to the epiproteome in response to cellular stimuli. These data have potential to revolutionize our understanding of biology and disease. This review covers a range of recent visualization methods and tools developed specifically for dynamic epiproteome data sets. These methods have been designed primarily for data sets on phosphorylation, as this the most studied PTM however, most of these methods are also applicable to other types of PTMs. Unfortunately, the currently available methods are often inadequate for existing data sets thus, realizing the potential buried in epiproteome data sets will require new, tailored bioinformatics methods that will help researchers analyze, visualize, and interactively explore these complex data sets.
Publisher: Springer Science and Business Media LLC
Date: 09-1996
DOI: 10.1007/BF00211165
Publisher: IEEE
Date: 09-2015
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.CELL.2015.04.041
Abstract: The insulin/IGF1signaling pathway (ISP) plays an essential role in long-term health. Some perturbations in this pathway are associated with diseases such as type 2 diabetes other perturbations extend lifespan in worms, flies, and mice. The ISP regulates many biological processes, including energy storage, apoptosis, transcription, and cellular homeostasis. Such regulation involves precise rewiring of temporal events in protein phosphorylation networks. For an animated version of this Enhanced SnapShot, please visit ell/enhanced/odonoghue.
Publisher: Wiley
Date: 04-1992
DOI: 10.1111/J.1432-1033.1992.TB16817.X
Abstract: We have developed algorithms for combining fluorescence resonance-energy transfer (FRET) efficiency measurements into structural models which predict the relative positions of the chemical groups used in FRET. We used these algorithms to construct models of the actin monomer and filament derived solely from FRET measurements based on seven distinct loci. We found a mirror-image pair of monomer models which best fit the FRET data. One of these models agrees well with the atomic-resolution crystal structure recently published by Kabsch et al. in Heidelberg [Kabsch, W., Mannherz, H. G., Suck, D., Pai, E. F. & Holmes, K. C. (1990) Nature 347, 37-44]. The root-mean-square deviation between this FRET model and the crystal structure was about 0.9 nm. Other macromolecular models assembled from FRET measurements are likely to have a similar resolution. The largest discrepancy was for the Cys10 locus which deviated 1.44 nm from the crystal position. We discuss the limitations of the FRET method that may have contributed to this discrepancy, and conclude that the Cys10 FRET data have probably located Cys10 incorrectly in the FRET monomer model. Using the FRET monomer models, we found three orientations in the filament which best fit the intermonomer FRET data. These orientations differ substantially from the atomic-resolution filament model proposed by the Heidelberg group [Holmes, K., Popp, D., Gebhard, W. & Kabsch, W. (1990) Nature 347, 44-49], largely because of the discrepancies in the Cys10 data. These data should probably be excluded from the analysis however, this would leave too few measurements to assemble a filament model. In the near future, we hope to obtain additional FRET measurements to other actin loci so that the filament modelling can be done without the Cys10 data.
Publisher: CRC Press
Date: 13-06-2006
Publisher: IEEE
Date: 10-2013
Publisher: Springer Science and Business Media LLC
Date: 07-1997
DOI: 10.1038/NSB0797-559
Abstract: A family of potent insecticidal toxins has recently been isolated from the venom of Australian funnel web spiders. Among these is the 37-residue peptide omega-atracotoxin-HV1 (omega-ACTX-HV1) from Hadronyche versuta. We have chemically synthesized and folded omega-ACTX-HV1, shown that it is neurotoxic, ascertained its disulphide bonding pattern, and determined its three-dimensional solution structure using NMR spectroscopy. The structure consists of a solvent-accessible beta-hairpin protruding from a disulphide-bonded globular core comprising four beta-turns. The three intramolecular disulphide bonds from a cystine knot motif similar to that seen in several other neurotoxic peptides. Despite limited sequence identity, omega-ACTX-HV1 displays significant structural homology with the omega-agatoxins and omega-conotoxins, both of which are vertebrate calcium channel antagonists however, in contrast with these toxins, we show that omega-ACTX-HV1 inhibits insect, but not mammalian, voltage-gated calcium channel currents.
Publisher: American Chemical Society (ACS)
Date: 06-1992
DOI: 10.1021/BI00139A030
Abstract: The aqueous solution structure of the 21-residue vasoactive peptide hormone endothelin-3 has been determined using high-resolution NMR spectroscopy. A total of 177 proton-proton distance measurements and 5 chi 1 dihedral angle constraints derived from NMR spectra were used to calculate the structure using a combination of distance geometry and dynamical simulated annealing calculations. The calculations reveal a highly ordered, compact conformation in which a helical region extending from K9 to C15 lies in close apposition with the C-terminal hexapeptide this interaction seems to be largely driven by hydrophobic interactions. Structure-activity studies are interpreted in terms of the conformational features of the calculated endothelin-3 structure.
Publisher: Oxford University Press (OUP)
Date: 2003
DOI: 10.1093/NAR/GKG110
Abstract: We introduce the PSSH ('Protein Sequence-to-Structure Homologies') database derived from HSSP2, an improved version of the HSSP ('Homology-derived Secondary Structure of Proteins') database [Dodge et al. (1998) Nucleic Acids Res., 26, 313-315]. Whereas each HSSP entry lists all protein sequences related to a given 3D structure, PSSH is the 'inverse', with each entry listing all structures related to a given sequence. In addition, we introduce two other derived databases: HSSPchain, in which each entry lists all sequences related to a given PDB chain, and HSSPalign, in which each entry gives details of one sequence aligned onto one PDB chain. This re-organization makes it easier to navigate from sequence to structure, and to map sequence features onto 3D structures. Currently (September 2002), PSSH provides structural information for over 400 000 protein sequences, covering 48% of SWALL and 61% of SWISS-PROT sequences HSSPchain provides sequence information for over 25 000 PDB chains, and HSSPalign gives over 14 million sequence-to-structure alignments. The databases can be accessed via SRS 3D, an extension to the SRS system, at srs3d.ebi.ac.uk/.
Publisher: Elsevier BV
Date: 02-1998
Abstract: In vivo, proteins occur in widely different physio-chemical environments, and, from in vitro studies, we know that protein structure can be very sensitive to environment. However, theoretical studies of protein structure have tended to ignore this complexity. In this paper, we have approached this problem by grouping proteins by their subcellular location and looking at structural properties that are characteristic to each location. We hypothesize that, throughout evolution, each subcellular location has maintained a characteristic physio-chemical environment, and that proteins in each location have adapted to these environments. If so, we would expect that protein structures from different locations will show characteristic differences, particularly at the surface, which is directly exposed to the environment. To test this hypothesis, we have examined all eukaryotic proteins with known three-dimensional structure and for which the subcellular location is known to be either nuclear, cytoplasmic, or extracellular. In agreement with previous studies, we find that the total amino acid composition carries a signal that identifies the subcellular location. This signal was due almost entirely to the surface residues. The surface residue signal was often strong enough to accurately predict subcellular location, given only a knowledge of which residues are at the protein surface. The results suggest how the accuracy of prediction of location from sequence can be improved. We concluded that protein surfaces show adaptation to their subcellular location. The nature of these adaptations suggests several principles that proteins may have used in adapting to particular physio-chemical environments these principles may be useful for protein design.
Publisher: American Chemical Society (ACS)
Date: 12-09-1995
DOI: 10.1021/BI00036A007
Abstract: Hamster dihydroorotase is the central domain of a trifunctional protein which has been cloned, overexpressed, and purified from Escherichia coli. Using the cDNA encoding the dihydroorotase domain, site-directed mutagenesis of amino acid residues conserved between species has enabled identification of three ligands of zinc at the catalytic site as His15, 17 and 158. The underlined amino acids of the nonapeptide sequence Ile12-Asp13-Val14-His15-Val16-His17- Leu18-Arg19-Glu20 from hamster are conserved between dihydroorotases from 8 species. It is proposed that the residues Asp13-His15-->ZnII form a triad at the active site and that Arg19, for which even the conservative mutation Arg19-->Lys yields an inactive enzyme, is involved in substrate binding. Site-directed mutagenesis of the conserved His186-->Ala yielded a mutant enzyme with a reduced affinity for 65Zn2+. The Km for dihydroorotate (DHO) increased from 4.0 to 11 microM, while the Vmax decreased from 1.2 to 0.53 mumol min-1 (mg of protein)-1, implicating this residue in only a minor way with binding of DHO and in catalysis. The mutation Asp230-->Glu resulted in a 14-fold increase in Km and a 16-fold decrease in Vmax, indicating involvement of this conserved residue in both binding and catalysis. The mutation Lys239-->Gly increased the Km for DHO 110-fold with a 2-fold increase in Vmax, suggesting that this residue may form a hydrogen bond with the substrate.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Elsevier BV
Date: 07-2010
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.CELL.2017.06.003
Abstract: During mitosis, a cell ides its duplicated genome into two identical daughter cells. This process must occur without errors to prevent proliferative diseases (e.g., cancer). A key mechanism controlling mitosis is the precise timing of more than 32,000 phosphorylation and dephosphorylation events by a network of kinases and counterbalancing phosphatases. The identity, magnitude, and temporal regulation of these events have emerged recently, largely from advances in mass spectrometry. Here, we show phosphoevents currently believed to be key regulators of mitosis. For an animated version of this SnapShot, please see ell/enhanced/odonoghue2.
Publisher: Elsevier BV
Date: 04-1998
Publisher: EMBO
Date: 09-2021
Publisher: Cold Spring Harbor Laboratory
Date: 14-04-2020
DOI: 10.1101/2020.04.14.040527
Abstract: Temporal changes in omics events can now be routinely measured, however current analysis methods are often inadequate, especially for multiomics experiments. We report a novel analysis method that can infer event ordering at better temporal resolution than the experiment, and integrates omic events into two concise visualizations (event maps and sparklines). Testing our method gave results well-correlated with prior knowledge and indicated it streamlines analysis of time-series data.
Publisher: Schloss Dagstuhl - Leibniz-Zentrum fuer Informatik GmbH, Wadern/Saarbruecken, Germany
Date: 2013
Publisher: Wiley
Date: 25-05-2006
DOI: 10.1002/PROT.20985
Abstract: Errors and imprecisions in distance restraints derived from NOESY peak volumes are usually accounted for by generous lower and upper bounds on the distances. In this paper, we propose a new form of distance restraints, replacing the subjective bounds by a potential function obtained from the error distribution of the distances. We derived the shape of the potential from molecular dynamics calculations and by comparison of NMR data with X-ray crystal structures. We used complete cross-validation to derive the optimal weight for the data in the calculation. In a model system with synthetic restraints, the accuracy of the structures improved significantly compared to calculations with the usual form of restraints. For experimental data sets, the structures systematically approach the X-ray crystal structures of the same protein. Also standard quality indicators improve compared to standard calculations. The results did not depend critically on the exact shape of the potential. The new approach is less subjective and uses fewer assumptions in the interpretation of NOESY peak volumes as distance restraints than the usual approach. Figures of merit for the structures, such as the RMS difference from the average structure or the RMS difference from the data, are therefore less biased and more meaningful measures of structure quality than with the usual form of restraints.
Publisher: Elsevier BV
Date: 09-2016
Publisher: Elsevier BV
Date: 02-1992
DOI: 10.1016/0003-9861(92)90372-4
Abstract: We define conditions under which the two C-terminal residues of actin, Cys-374 and Phe-375, can be selectively removed by proteolysis with trypsin. This modification had little effect on the secondary structure of actin detected by Fourier-transform infrared spectroscopy. However, removing these residues caused small but significant decreases in the critical concentration of actin, in its ability to activate myosin ATPase, and in its interaction with tropomyosin and troponin. Removing residues 374-375 caused dramatic changes in the actin filament as seen by electron microscopy. The filaments had a much greater and more irregular curvature and were intertwined into disordered multifilament bundles. Removing 374-375 also significantly lowered the flow viscosity of filamentous-actin solutions. These data suggest an increase in the flexibility and fragility of the filament, supporting the idea that the C-terminus forms one of the major intermonomer contacts in the filament.
Publisher: PeerJ
Date: 30-06-2015
DOI: 10.7717/PEERJ.1054
Publisher: Springer International Publishing
Date: 13-10-2014
DOI: 10.1007/978-3-319-10984-8_1
Abstract: Data visualisation is usually a crucial first step in analysing and exploring large-scale complex data. The visualisation of proteomics time-course data on post-translational modifications presents a particular challenge that is largely unmet by existing tools and methods. To this end, we present Minardo, a novel visualisation strategy tailored for such proteomics data, in which data layout is driven by both cellular topology and temporal order. In this work, we utilised the Minardo strategy to visualise a dataset showing phosphorylation events in response to insulin. We evaluated the visualisation together with experts in diabetes and obesity, which led to new insights into the insulin response pathway. Based on this success, we outline how this layout strategy could be automated into a web-based tool for visualising a broad range of proteomics time-course data. We also discuss how the approach could be extended to include protein 3D structure information, as well as higher dimensional data, such as a range of experimental conditions. We also discuss our entry of Minardo in the international DREAM8 competition.
Publisher: AIP
Date: 2013
DOI: 10.1063/1.4825010
Publisher: AIP
Date: 2013
DOI: 10.1063/1.4825252
Publisher: Cold Spring Harbor Laboratory
Date: 17-07-2020
DOI: 10.1101/2020.07.16.207308
Abstract: In response to the COVID-19 pandemic, many life scientists are focused on SARS-CoV-2. To help them use available structural data, we systematically modeled all viral proteins using all related 3D structures, generating 872 models that provide detail not available elsewhere. To organise these models, we created a structural coverage map: a novel, one-stop visualization summarizing what is — and is not — known about the 3D structure of the viral proteome. The map highlights structural evidence for viral protein interactions, mimicry, and hijacking it also helps researchers find 3D models of interest, which can then be mapped with UniProt, PredictProtein, or CATH features. The resulting Aquaria-COVID resource ( aquaria.ws/covid ) helps scientists understand molecular mechanisms underlying coronavirus infection. Based on insights gained using our resource, we propose mechanisms by which the virus may enter immune cells, sense the cell type, then switch focus from viral reproduction to disrupting host immune responses. Currently, much of the COVID-19 viral proteome has unknown molecular structure. To improve this, we generated ∼1,000 structural models, designed to capture multiple states for each viral protein. To organise these models, we created a structure coverage map: a novel, one-stop visualization summarizing what is — and is not — known about viral protein structure. We used these data to create an online resource, designed to help COVID-19 researchers gain insight into the key molecular processes that drive infection. Based on insights gained using our resource, we speculate that the virus may sense the type of cells it infects and, within certain cells, it may switch from reproduction to disruption of the immune system.
Publisher: Springer Science and Business Media LLC
Date: 02-2012
Abstract: Keeping up-to-date with bioscience literature is becoming increasingly challenging. Several recent methods help meet this challenge by allowing literature search to be launched based on lists of abstracts that the user judges to be 'interesting'. Some methods go further by allowing the user to provide a second input set of 'uninteresting' abstracts these two input sets are then used to search and rank literature by relevance. In this work we present the service 'Caipirini' ( caipirini.org ) that also allows two input sets, but takes the novel approach of allowing ranking of literature based on one or more sets of genes. To evaluate the usefulness of Caipirini, we used two test cases, one related to the human cell cycle, and a second related to disease defense mechanisms in Arabidopsis thaliana . In both cases, the new method achieved high precision in finding literature related to the biological mechanisms underlying the input data sets. To our knowledge Caipirini is the first service enabling literature search directly based on biological relevance to gene sets thus, Caipirini gives the research community a new way to unlock hidden knowledge from gene sets derived via high-throughput experiments.
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.YMETH.2014.07.004
Abstract: As the amount of genome information increases rapidly, there is a correspondingly greater need for methods that provide accurate and automated annotation of gene function. For ex le, many high-throughput technologies--e.g., next-generation sequencing--are being used today to generate lists of genes associated with specific conditions. However, their functional interpretation remains a challenge and many tools exist trying to characterize the function of gene-lists. Such systems rely typically in enrichment analysis and aim to give a quick insight into the underlying biology by presenting it in a form of a summary-report. While the load of annotation may be alleviated by such computational approaches, the main challenge in modern annotation remains to develop a systems form of analysis in which a pipeline can effectively analyze gene-lists quickly and identify aggregated annotations through computerized resources. In this article we survey some of the many such tools and methods that have been developed to automatically interpret the biological functions underlying gene-lists. We overview current functional annotation aspects from the perspective of their epistemology (i.e., the underlying theories used to organize information about gene function into a body of verified and documented knowledge) and find that most of the currently used functional annotation methods fall broadly into one of two categories: they are based either on 'known' formally-structured ontology annotations created by 'experts' (e.g., the GO terms used to describe the function of Entrez Gene entries), or--perhaps more adventurously--on annotations inferred from literature (e.g., many text-mining methods use computer-aided reasoning to acquire knowledge represented in natural languages). Overall however, deriving detailed and accurate insight from such gene lists remains a challenging task, and improved methods are called for. In particular, future methods need to (1) provide more holistic insight into the underlying molecular systems (2) provide better follow-up experimental testing and treatment options, and (3) better manage gene lists derived from organisms that are not well-studied. We discuss some promising approaches that may help achieve these advances, especially the use of extended dictionaries of biomedical concepts and molecular mechanisms, as well as greater use of annotation benchmarks.
Publisher: Cold Spring Harbor Laboratory
Date: 06-04-2016
Abstract: A three-dimensional chromatin state underpins the structural and functional basis of the genome by bringing regulatory elements and genes into close spatial proximity to ensure proper, cell-type–specific gene expression profiles. Here, we performed Hi-C chromosome conformation capture sequencing to investigate how three-dimensional chromatin organization is disrupted in the context of copy-number variation, long-range epigenetic remodeling, and atypical gene expression programs in prostate cancer. We find that cancer cells retain the ability to segment their genomes into megabase-sized topologically associated domains (TADs) however, these domains are generally smaller due to establishment of additional domain boundaries. Interestingly, a large proportion of the new cancer-specific domain boundaries occur at regions that display copy-number variation. Notably, a common deletion on 17p13.1 in prostate cancer spanning the TP53 tumor suppressor locus results in bifurcation of a single TAD into two distinct smaller TADs. Change in domain structure is also accompanied by novel cancer-specific chromatin interactions within the TADs that are enriched at regulatory elements such as enhancers, promoters, and insulators, and associated with alterations in gene expression. We also show that differential chromatin interactions across regulatory regions occur within long-range epigenetically activated or silenced regions of concordant gene activation or repression in prostate cancer. Finally, we present a novel visualization tool that enables integrated exploration of Hi-C interaction data, the transcriptome, and epigenome. This study provides new insights into the relationship between long-range epigenetic and genomic dysregulation and changes in higher-order chromatin interactions in cancer.
Publisher: Cold Spring Harbor Laboratory
Date: 24-02-2021
DOI: 10.1101/2021.02.23.432527
Abstract: Since 1992 PredictProtein ( predictprotein.org ) is a one-stop online resource for protein sequence analysis with its main site hosted at the Luxembourg Centre for Systems Biomedicine (LCSB) and queried monthly by over 3,000 users in 2020. PredictProtein was the first Internet server for protein predictions. It pioneered combining evolutionary information and machine learning. Given a protein sequence as input, the server outputs multiple sequence alignments, predictions of protein structure in 1D and 2D (secondary structure, solvent accessibility, transmembrane segments, disordered regions, protein flexibility, and disulfide bridges) and predictions of protein function (functional effects of sequence variation or point mutations, Gene Ontology (GO) terms, subcellular localization, and protein-, RNA-, and DNA binding). PredictProtein’s infrastructure has moved to the LCSB increasing throughput the use of MMseqs2 sequence search reduced runtime five-fold user interface elements improved usability, and new prediction methods were added. PredictProtein recently included predictions from deep learning embeddings (GO and secondary structure) and a method for the prediction of proteins and residues binding DNA, RNA, or other proteins. PredictProtein.org aspires to provide reliable predictions to computational and experimental biologists alike. All scripts and methods are freely available for offline execution in high-throughput settings. Freely accessible webserver PredictProtein.org Source and docker images: ostlab
Publisher: Springer Science and Business Media LLC
Date: 13-08-2015
Publisher: Elsevier BV
Date: 06-1997
DOI: 10.1016/S1359-0278(97)00063-1
Abstract: We report a preliminary study of the use of mean-force potentials (MFPs) for predicting protein tertiary structure. For three leucine zipper sequences, we have calculated ensembles of structures spanning all possible backbone conformations consistent with the canonical coiled-coil geometry. MFPs were measured with the program PROSA. The MFP alone was poor at discriminating the native structure from very ergent structures, and the global minimum of the MFP sometimes occurred far from the native structure. We found that adding an internal energy function (a subset of the CHARMM potential that describes only interactions between backbone atoms), the resultant total energy (CHARMM+PROSA) performed much better in each case, there was a clear positive correlation between total energy and root-mean-square deviation (RMSD) from the experimental structure, and the lowest-energy structures were about 1 A RMSD from the experimental structures. Thus, we conclude that the combined potential is a powerful method for predicting leucine zippers and is very promising for general 3D structure prediction.
Publisher: Springer Science and Business Media LLC
Date: 2002
Abstract: Surfactant protein D (SP-D) is one of four known protein components of the pulmonary surfactant lining the lung alveoli. It is involved in immune and allergic responses. SP-D occurs as a tetramer of trimers. Trimerization is thought to be initiated by a coiled coil domain. We have determined the solution structure of a 64-residue peptide encompassing the coiled coil domain of human SP-D. As predicted, the domain forms a triple-helical parallel coiled coil. As with all symmetric oligomers, the structure calculation was complicated by the symmetry degeneracy in the NMR spectra. We used the symmetry-ADR (ambiguous distance restraint) structure calculation method to solve the structure. The results demonstrate that the leucine zipper region of SP-D is an autonomously folded domain. The structure is very similar to the independently determined X-ray crystal structure, differing mainly at a single residue, Tyr248. This residue is completely symmetric in the solution structure, and markedly asymmetric in the crystalline phase. This difference may be functionally important, as it affects the orientation of the antigenic surface presented by SP-D.
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.CELL.2019.09.031
Abstract: S-phase entry and exit are regulated by hundreds of protein complexes that assemble "just in time," orchestrated by a multitude of distinct events. To help understand their interplay, we have created a tailored visualization based on the Minardo layout, highlighting over 80 essential events. This complements our earlier visualization of M-phase, and both can be displayed together, giving a comprehensive overview of the events regulating the cell ision cycle. To view this SnapShot, open or download the PDF.
Publisher: Springer Science and Business Media LLC
Date: 2008
Publisher: Oxford University Press (OUP)
Date: 24-10-2009
DOI: 10.1093/NAR/GKP876
Publisher: Oxford University Press (OUP)
Date: 1991
Publisher: Public Library of Science (PLoS)
Date: 15-06-2010
Publisher: Wiley
Date: 05-03-2002
DOI: 10.1016/S0014-5793(02)02466-3
Abstract: Nuclear magnetic resonance (NMR) spectroscopy reveals that higher-order aggregates of glucagon-like peptide-1-(7-36)-amide (GLP-1) in pure water at pH 2.5 are disrupted by 35% 2,2,2-trifluoroethanol (TFE), and form a stable and highly symmetric helical self-aggregate. NMR spectra show that the helical structure is identical to that formed by monomeric GLP-1 under the same experimental conditions [Chang et al., Magn. Reson. Chem. 37 (2001) 477-483 Protein Data Bank at RCSB code: 1D0R], while amide proton exchange rates reveal a dramatic increase of the stability of the helices of the self-aggregate. Pulsed-field gradient NMR diffusion experiments show that the TFE-induced helical self-aggregate is a dimer. The experimental data and model calculations indicate that the dimer is a parallel coiled coil, with a few hydrophobic residues on the surface that may cause aggregation in pure water. The results suggest that the coiled coil dimer is an intermediate state towards the formation of higher aggregates, e.g. fibrils.
Publisher: ACM Press
Date: 2016
Publisher: Elsevier BV
Date: 05-2001
Abstract: ARM and HEAT motifs are tandemly repeated sequences of approximately 50 amino acid residues that occur in a wide variety of eukaryotic proteins. An exhaustive search of sequence databases detected new family members and revealed that at least 1 in 500 eukaryotic protein sequences contain such repeats. It also rendered the similarity between ARM and HEAT repeats, believed to be evolutionarily related, readily apparent. All the proteins identified in the database searches could be clustered by sequence similarity into four groups: canonical ARM-repeat proteins and three groups of the more ergent HEAT-repeat proteins. This allowed us to build improved sequence profiles for the automatic detection of repeat motifs. Inspection of these profiles indicated that the in idual repeat motifs of all four classes share a common set of seven highly conserved hydrophobic residues, which in proteins of known three-dimensional structure are buried within or between repeats. However, the motifs differ at several specific residue positions, suggesting important structural or functional differences among the classes. Our results illustrate that ARM and HEAT-repeat proteins, while having a common phylogenetic origin, have since erged significantly. We discuss evolutionary scenarios that could account for the great ersity of repeats observed.
Publisher: Springer Science and Business Media LLC
Date: 16-07-2020
DOI: 10.1038/S41540-020-0141-0
Abstract: Temporal changes in omics events can now be routinely measured however, current analysis methods are often inadequate, especially for multiomics experiments. We report a novel analysis method that can infer event ordering at better temporal resolution than the experiment, and integrates omic events into two concise visualizations (event maps and sparklines). Testing our method gave results well-correlated with prior knowledge and indicated it streamlines analysis of time-series data.
Publisher: American Chemical Society (ACS)
Date: 29-03-1994
DOI: 10.1021/BI00178A011
Abstract: The specificity of glyoxalase 1 for the diastereomers of its hemithioacetal substrate [which forms spontaneously between an alpha-keto aldehyde and reduced glutathione (GSH)] was investigated by exploiting the differences between their 1H NMR spectra at pH* 4.4. The 1H NMR spectra of the hemithioacetals of glutathione with phenylglyoxal or methylglyoxal were assigned with the aid of conventional decoupling and two-dimensional NMR spectroscopic techniques. The rate of interconversion of the diastereomers was determined at 30 degrees C from the results of an inversion-transfer technique and found to be 0.30 +/- 0.04 s-1 (+/- sd) in the case of phenylglyoxal and 0.15 +/- 0.02 s-1 in the case of methylglyoxal. Stereopreference of the enzyme was tested by the addition of large amounts of yeast glyoxalase 1 to a reaction mixture glyoxalase 1 preferentially operated on one diastereomer of the phenylglyoxal hemithioacetal but the diastereomers of methylglyoxal appeared to be operated upon indiscriminately. From computer models of the kinetics of possible reaction schemes, a mechanism involving glyoxalase 1 catalysis of both diastereomers of the hemithioacetals was shown to be the most consistent with the experimental data. Estimates of internuclear distances in the diastereomers, obtained from 2D NMR spectra were used in "dynamical simulated annealing" calculations to generate likely structures of the substrates. Relative ring-current shifts obtained from 1D NMR spectra were used, together with a ring-current shift algorithm, to select structures with compatible conformations. We conclude that the rate of conversion of substrate by the enzyme is dependent upon the overall conformation of the substrate molecule, rather than merely its stereochemical configuration (R or S).
Publisher: Springer Science and Business Media LLC
Date: 20-07-2017
Publisher: Springer Science and Business Media LLC
Date: 06-2009
DOI: 10.1038/NBT0609-508
Publisher: Oxford University Press (OUP)
Date: 1997
DOI: 10.1093/BIOINFORMATICS/13.4.345
Abstract: The problem of predicting protein structure from the sequence remains fundamentally unsolved despite more than three decades of intensive research effort. However, new and promising methods in three-dimensional (3D), 2D and 1D prediction have reopened the field. Mean-force-potentials derived from the protein databases can distinguish between correct and incorrect models (3D). Inter-residue contacts (2D) can be detected by analysis of correlated mutations, albeit with low accuracy. Secondary structure, solvent accessibility and transmembrane helices (1D) can be predicted with significantly improved accuracy using multiple sequence alignments. Some of these new prediction methods have proven accurate and reliable enough to be useful in genome analysis, and in experimental structure determination. Moreover, the new generation of theoretical methods is increasingly influencing experiments in molecular biology.
Publisher: Elsevier BV
Date: 06-1996
Publisher: Wiley
Date: 03-1999
DOI: 10.1002/(SICI)1097-0134(19990301)34:4<453::AID-PROT5>3.0.CO;2-7
Publisher: Elsevier
Date: 2001
No related grants have been discovered for Sean O'Donoghue.