Genome3D: exploiting structure to help users understand their sequences.
Nucleic Acids Res. 2014 Oct 27;
Authors: Lewis TE, Sillitoe I, Andreeva A, Blundell TL, Buchan DW, Chothia C, Cozzetto D, Dana JM, Filippis I, Gough J, Jones DT, Kelley LA, Kleywegt GJ, Minneci F, Mistry J, Murzin AG, Ochoa-Montaño B, Oates ME, Punta M, Rackham OJ, Stahlhacke J, Sternberg MJ, Velankar S, Orengo C
Genome3D (http://www.genome3d.eu) is a collaborative resource that provides predicted domain annotations and structural models for key sequences. Since introducing Genome3D in a previous NAR paper, we have substantially extended and improved the resource. We have annotated representatives from Pfam families to improve coverage of diverse sequences and added a fast sequence search to the website to allow users to find Genome3D-annotated sequences similar to their own. We have improved and extended the Genome3D data, enlarging the source data set from three model organisms to 10, and adding VIVACE, a resource new to Genome3D. We have analysed and updated Genome3D's SCOP/CATH mapping. Finally, we have improved the superposition tools, which now give users a more powerful interface for investigating similarities and differences between structural models.
PMID: 25348407 [PubMed - as supplied by publisher]
Platinum: a database of experimentally measured effects of mutations on structurally defined protein-ligand complexes.
Nucleic Acids Res. 2014 Oct 16;
Authors: Pires DE, Blundell TL, Ascher DB
Drug resistance is a major challenge for the treatment of many diseases and a significant concern throughout the drug development process. The ability to understand and predict the effects of mutations on protein-ligand affinities and their roles in the emergence of resistance would significantly aid treatment and drug design strategies. In order to study and understand the impacts of missense mutations on the interaction of ligands with the proteome, we have developed Platinum (http://structure.bioc.cam.ac.uk/platinum). This manually curated, literature-derived database, comprising over 1000 mutations, associates for the first time experimental information on changes in affinity with three-dimensional structures of protein-ligand complexes. To minimize differences arising from experimental techniques and to directly compare binding affinities, Platinum considers only changes measured by the same group and with the same amino-acid sequence used for structure determination, providing a direct link between protein structure, how a ligand binds and how mutations alter the affinity of the ligand of the protein. We believe Platinum will be an invaluable resource for understanding the effects of mutations that give rise to drug resistance, a major problem emerging in pandemics including those caused by the influenza virus, in infectious diseases such as tuberculosis, in cancer and in many other life-threatening illnesses.
PMID: 25324307 [PubMed - as supplied by publisher]
Polyphony: superposition independent methods for ensemble-based drug discovery.
BMC Bioinformatics. 2014 Sep 30;15(1):324
Authors: Pitt WR, Montalvão RW, Blundell TL
BACKGROUND: Structure-based drug design is an iterative process, following cycles of structural biology, computer-aided design, synthetic chemistry and bioassay. In favorable circumstances, this process can lead to the structures of hundreds of protein-ligand crystal structures. In addition, molecular dynamics simulations are increasingly being used to further explore the conformational landscape of these complexes. Currently, methods capable of the analysis of ensembles of crystal structures and MD trajectories are limited and usually rely upon least squares superposition of coordinates.
RESULTS: Novel methodologies are described for the analysis of multiple structures of the same or related proteins. Statistical approaches that rely upon residue equivalence, but not superposition, are developed. Tasks that can be performed include the identification of hinge regions, allosteric conformational changes and transient binding sites. The approaches are tested on crystal structures of CDK2 and other CMGC protein kinases and a simulation of p38alpha. Known interaction - conformational change relationships are highlighted but also new ones are revealed. A transient but druggable allosteric pocket in CDK2 is predicted to occur under the CMGC insert. Furthermore, an evolutionarily-conserved conformational link from the location of this pocket, via the alphaEF-alphaF loop, to phosphorylation sites on the activation loop is discovered.
CONCLUSIONS: New methodologies are described and validated for the superimposition independent conformational analysis of large collections of structures or simulation snapshots of the same protein. The methodologies are encoded in a Python package called Polyphony, which is released as open source to accompany this paper [http://wrpitt.bitbucket.org/polyphony/].
PMID: 25265915 [PubMed - as supplied by publisher]
Design and Structural Analysis of Aromatic Inhibitors of Type II Dehydroquinase from Mycobacterium tuberculosis.
ChemMedChem. 2014 Sep 18;
Authors: Howard NI, Dias MV, Peyrot F, Chen L, Schmidt MF, Blundell TL, Abell C
3-Dehydroquinase, the third enzyme in the shikimate pathway, is a potential target for drugs against tuberculosis. Whilst a number of potent inhibitors of the Mycobacterium tuberculosis enzyme based on a 3-dehydroquinate core have been identified, they generally show little or no in vivo activity, and were synthetically complex to prepare. This report describes studies to develop tractable and drug-like aromatic analogues of the most potent inhibitors. A range of carbon-carbon linked biaryl analogues were prepared to investigate the effect of hydrogen bond acceptor and donor patterns on inhibition. These exhibited inhibitory activity in the high-micromolar range. The addition of flexible linkers in the compounds led to the identification of more potent 3-nitrobenzylgallate- and 5-aminoisophthalate-based analogues.
PMID: 25234229 [PubMed - as supplied by publisher]