PeptiSite: a structural database of peptide binding sites in 4D.

We developed PeptiSite, a comprehensive and reliable database of biologically and structurally characterized peptide-binding sites, in which each site is represented by an ensemble of its complexes with protein, peptide and small molecule partners. The unique features of the database include: (1) the ensemble site representation that provides a fourth dimension to the otherwise three dimensional data, (2) comprehensive characterization of the binding site architecture that may consist of a multimeric protein assembly with cofactors and metal ions and (3) analysis of consensus interaction motifs within the ensembles and identification of conserved determinants of these interactions. Currently the database contains 585 proteins with 650 peptide-binding sites. http://peptisite.ucsd.edu/ link allows searching for the sites of interest and interactive visualization of the ensembles using the ActiveICM web-browser plugin. This structural database for protein-peptide interactions enables understanding of structural principles of these interactions and may assist the development of an efficient peptide docking benchmark.

[1]  Richard A. Lewis,et al.  Lessons in molecular recognition: the effects of ligand and protein flexibility on molecular docking accuracy. , 2004, Journal of medicinal chemistry.

[2]  Thomas Lengauer,et al.  FlexE: efficient molecular docking considering protein structure variations. , 2001, Journal of molecular biology.

[3]  Roland L. Dunbrack,et al.  Conformational analysis of the backbone-dependent rotamer preferences of protein sidechains , 1994, Nature Structural Biology.

[4]  Brian K. Shoichet,et al.  Structure-Based Discovery of A2A Adenosine Receptor Ligands , 2010, Journal of medicinal chemistry.

[5]  M. Sternberg,et al.  An analysis of conformational changes on protein-protein association: implications for predictive docking. , 1999, Protein engineering.

[6]  R Nussinov,et al.  Flexible docking allowing induced fit in proteins: Insights from an open to closed conformational isomers , 1998, Proteins.

[7]  Claudio N. Cavasotto,et al.  Protein flexibility in ligand docking and virtual screening to protein kinases. , 2004, Journal of molecular biology.

[8]  Ruben Abagyan,et al.  Interactive JIMD articles using the iSee concept: turning a new page on structural biology data , 2011, Journal of Inherited Metabolic Disease.

[9]  Ruben Abagyan,et al.  Analysis of full and partial agonists binding to β2‐adrenergic receptor suggests a role of transmembrane helix V in agonist‐specific conformational changes , 2009, Journal of molecular recognition : JMR.

[10]  Robert B. Russell,et al.  Combinations of Protein-Chemical Complex Structures Reveal New Targets for Established Drugs , 2011, PLoS Comput. Biol..

[11]  Benjamin A. Shoemaker,et al.  Inferred Biomolecular Interaction Server—a web server to analyze and predict protein interacting partners and binding sites , 2009, Nucleic Acids Res..

[12]  Eduardo Garcia Urdiales,et al.  Accurate Prediction of Peptide Binding Sites on Protein Surfaces , 2009, PLoS Comput. Biol..

[13]  R. Abagyan,et al.  Type-II kinase inhibitor docking, screening, and profiling using modified structures of active kinase states. , 2008, Journal of medicinal chemistry.

[14]  Gustavo D. Parisi,et al.  PCDB: a database of protein conformational diversity , 2010, Nucleic Acids Res..

[15]  Robin Taylor,et al.  A new test set for validating predictions of protein–ligand interaction , 2002, Proteins.

[16]  R. Abagyan,et al.  The flexible pocketome engine for structural chemogenomics. , 2009, Methods in molecular biology.

[17]  François Stricher,et al.  PepX: a structural database of non-redundant protein–peptide complexes , 2009, Nucleic Acids Res..

[18]  Holger Gohlke,et al.  Change in protein flexibility upon complex formation: Analysis of Ras‐Raf using molecular dynamics and a molecular framework approach , 2004, Proteins.

[19]  Ruben Abagyan,et al.  Pocketome: an encyclopedia of small-molecule binding sites in 4D , 2011, Nucleic Acids Res..

[20]  J J Baldwin,et al.  Application of the three-dimensional structures of protein target molecules in structure-based drug design. , 1994, Journal of medicinal chemistry.

[21]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[22]  Ruben Abagyan,et al.  Structure-based discovery of novel chemotypes for adenosine A(2A) receptor antagonists. , 2010, Journal of medicinal chemistry.

[23]  R. Abagyan,et al.  Flexible ligand docking to multiple receptor conformations: a practical alternative. , 2008, Current opinion in structural biology.

[24]  W. Howe,et al.  Computer design of bioactive molecules: A method for receptor‐based de novo ligand design , 1991, Proteins.

[25]  D S Goodsell,et al.  Automated docking of flexible ligands: Applications of autodock , 1996, Journal of molecular recognition : JMR.

[26]  Andrew R. Leach,et al.  Molecular Complexity and Its Impact on the Probability of Finding Leads for Drug Discovery , 2001, J. Chem. Inf. Comput. Sci..

[27]  Richard D. Smith,et al.  Binding MOAD, a high-quality protein–ligand database , 2007, Nucleic Acids Res..

[28]  D. Rognan,et al.  Selective structure-based virtual screening for full and partial agonists of the beta2 adrenergic receptor. , 2008, Journal of medicinal chemistry.

[29]  M Kokkinidis,et al.  Protein plasticity to the extreme: changing the topology of a 4-alpha-helical bundle with a single amino acid substitution. , 1999, Structure.

[30]  J. Kuriyan,et al.  The Conformational Plasticity of Protein Kinases , 2002, Cell.

[31]  Roland L. Dunbrack,et al.  Backbone-dependent rotamer library for proteins. Application to side-chain prediction. , 1993, Journal of molecular biology.

[32]  Philip E. Bourne,et al.  IEDB-3D: structural data within the immune epitope database , 2010, Nucleic Acids Res..

[33]  B. Matthews,et al.  Specificity of ligand binding in a buried nonpolar cavity of T4 lysozyme: linkage of dynamics and structural plasticity. , 1995, Biochemistry.

[34]  Leslie A Kuhn,et al.  Side‐chain flexibility in protein–ligand binding: The minimal rotation hypothesis , 2005, Protein science : a publication of the Protein Society.

[35]  Rafael Najmanovich,et al.  Side‐chain flexibility in proteins upon ligand binding , 2000, Proteins.

[36]  R. Abagyan,et al.  Systematic Exploitation of Multiple Receptor Conformations for Virtual Ligand Screening , 2011, PloS one.

[37]  Markus Wagener,et al.  A flexible approach to induced fit docking. , 2007, Journal of medicinal chemistry.

[38]  R. Nussinov,et al.  The role of dynamic conformational ensembles in biomolecular recognition. , 2009, Nature chemical biology.

[39]  Didier Rognan,et al.  Customizing G Protein-coupled receptor models for structure-based virtual screening. , 2009, Current pharmaceutical design.

[40]  David S. Wishart,et al.  DrugBank: a knowledgebase for drugs, drug actions and drug targets , 2007, Nucleic Acids Res..

[41]  Heather A Carlson,et al.  Protein flexibility is an important component of structure-based drug discovery. , 2002, Current pharmaceutical design.

[42]  Tin Wee Tan,et al.  MPID: MHC-Peptide Interaction Database for sequence-structure-function information on peptides binding to MHC molecules , 2003, Bioinform..

[43]  R. Friesner,et al.  Novel procedure for modeling ligand/receptor induced fit effects. , 2006, Journal of medicinal chemistry.

[44]  R. Babine,et al.  MOLECULAR RECOGNITION OF PROTEIN-LIGAND COMPLEXES : APPLICATIONS TO DRUG DESIGN , 1997 .

[45]  Samuel H. Gellman,et al.  Introduction: Molecular Recognition. , 1997, Chemical reviews.

[46]  Ruben Abagyan,et al.  A New Method for Publishing Three-Dimensional Content , 2009, PloS one.

[47]  P Willett,et al.  Development and validation of a genetic algorithm for flexible docking. , 1997, Journal of molecular biology.

[48]  Gisbert Schneider,et al.  Computer-based de novo design of drug-like molecules , 2005, Nature Reviews Drug Discovery.

[49]  D Schomburg,et al.  Three-dimensional structure of a recombinant variant of human pancreatic secretory trypsin inhibitor (Kazal type). , 1992, Journal of molecular biology.

[50]  Andrew Chatr-aryamontri,et al.  DOMINO: a database of domain–peptide interactions , 2006, Nucleic Acids Res..

[51]  Michael M. Mysinger,et al.  Automated Docking Screens: A Feasibility Study , 2009, Journal of medicinal chemistry.

[52]  I. Kuntz,et al.  Molecular docking to ensembles of protein structures. , 1997, Journal of molecular biology.

[53]  Teruki Honma,et al.  Recent advances in de novo design strategy for practical lead identification , 2003, Medicinal research reviews.

[54]  Philip M Dean,et al.  Efficient conformational sampling of local side-chain flexibility. , 2003, Journal of molecular biology.

[55]  M. James,et al.  Crystallographic analysis of transition-state mimics bound to penicillopepsin: phosphorus-containing peptide analogues. , 1993, Biochemistry.

[56]  Ruben Abagyan,et al.  Disseminating structural genomics data to the public: from a data dump to an animated story. , 2006, Trends in biochemical sciences.

[57]  Marcel L. Verdonk,et al.  Sensitivity of molecular docking to induced fit effects in influenza virus neuraminidase , 2002, J. Comput. Aided Mol. Des..

[58]  C. Murray,et al.  The rise of fragment-based drug discovery. , 2009, Nature chemistry.

[59]  Gerhard Klebe,et al.  Utilising structural knowledge in drug design strategies: applications using Relibase. , 2003, Journal of molecular biology.

[60]  A. Wand,et al.  Conformational entropy in molecular recognition by proteins , 2007, Nature.

[61]  K. Soppimath,et al.  Novel delivery technologies for protein and peptide therapeutics. , 2006, Current pharmaceutical biotechnology.

[62]  J M Blaney,et al.  A geometric approach to macromolecule-ligand interactions. , 1982, Journal of molecular biology.

[63]  B. Shoichet,et al.  Soft docking and multiple receptor conformations in virtual screening. , 2004, Journal of medicinal chemistry.

[64]  A. Lesk,et al.  Elbow motion in the immunoglobulins involves a molecular ball-and-socket joint , 1988, Nature.

[65]  Ruben Abagyan,et al.  Four-dimensional docking: a fast and accurate account of discrete receptor flexibility in ligand docking. , 2009, Journal of medicinal chemistry.

[66]  Roland L. Dunbrack,et al.  Prediction of protein side-chain rotamers from a backbone-dependent rotamer library: a new homology modeling tool. , 1997, Journal of molecular biology.

[67]  I. Kuntz.  Structure-Based Strategies for Drug Design and Discovery , 1992, Science.

[68]  H. Carlson.  Protein flexibility and drug design: how to hit a moving target. , 2002, Current opinion in chemical biology.

[69]  S. Teague.  Implications of protein flexibility for drug discovery , 2003, Nature Reviews Drug Discovery.

[70]  R. Abagyan,et al.  Pocketome via Comprehensive Identification and Classification of Ligand Binding Envelopes* , 2005, Molecular & Cellular Proteomics.