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Crystallographic studies of substrates and inhibitors bound to the active site of alpha-chymotrypsin","volume":"2","author":"TA Steitz","year":"1969","journal-title":"J Mol Biol"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1126\/science.1546324","article-title":"Converting trypsin to chymotrypsin \u2013 the role of surface loops","volume":"5049","author":"L Hedstrom","year":"1992","journal-title":"Science"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"29987","DOI":"10.1074\/jbc.272.48.29987","article-title":"Evolutionary Divergence of Substrate Specificity within the Chymotrypsin-like Serine Protease Fold","volume":"48","author":"JJ Perona","year":"1997","journal-title":"J Biol Chem"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1529\/biophysj.104.057158","article-title":"Specificity of Trypsin and Chymotrypsin: Loop-Motion-Controlled Dynamic Correlation as a Determinant","volume":"89","author":"W Ma","year":"2005","journal-title":"Biophys J"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1111\/j.1432-1033.1991.tb16163.x","article-title":"The specificity of chymotrypsin","volume":"199","author":"V Schellenberger","year":"1991","journal-title":"Eur J Biochem"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1021\/bi00431a001","article-title":"Human Leukocyte and Porcine Pancreatic Elastase: X-ray Crystal Structures, Mechanism, Substrate Specificity, and Mechanism-Based Inhibitors","volume":"5","author":"W Bode","year":"1989","journal-title":"Biochemistry"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1006\/jmbi.1999.3089","article-title":"Crystal Structure of Enteropeptidase light Chain Complexed with an Analog of the Trypsinogen Activation Peptide","volume":"292","author":"D Lu","year":"1999","journal-title":"J Mol Biol"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1002\/pro.5560040301","article-title":"Structural basis of substrate specificity in the serine proteases","volume":"4","author":"JJ Perona","year":"1995","journal-title":"Protein Sci"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.tibs.2009.04.001","article-title":"SitePredicting the cleavage of proteinase substrates","volume":"7","author":"J Verspurten","year":"2009","journal-title":"Trends Biochem Sci"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.cbpa.2006.11.021","article-title":"Methods for mapping protease specificity","volume":"11","author":"SL Diamond","year":"2007","journal-title":"Curr Opin Chem Biol"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"3968","DOI":"10.2174\/092986710793205381","article-title":"Current strategies for probing substrate specificity of proteases","volume":"17","author":"M Poreba","year":"2010","journal-title":"Curr Med Chem"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"7754","DOI":"10.1073\/pnas.140132697","article-title":"Rapid and general profiling of protease specificity by using combinatorial fluorogenic substrate libraries","volume":"14","author":"JL Harris","year":"2000","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/nbt.1611","article-title":"Isotopic labeling of terminal amines in complex samples identifies protein N-termini and protease cleavage products","volume":"3","author":"O Kleifeld","year":"2010","journal-title":"Nat Biotechnol"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1042\/BJ20070775","article-title":"Profiling constitutive proteolytic events in vivo","volume":"407","author":"JC Timmer","year":"2007","journal-title":"Biochem 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substrate specificity with solution phase fluorogenic peptide microarrays","volume":"5","author":"DN Gosalia","year":"2005","journal-title":"Proteomics"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/nbt1408","article-title":"Proteome-derived, database-searchable peptide libraries for identifying protease cleavage sites","volume":"6","author":"O Schilling","year":"2008","journal-title":"Nat Biotechnol"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1515\/BC.2011.158","article-title":"Factor Xa subsite mapping by proteome-derived peptide libraries improved using WebPICS, a resource for proteomic identification of cleavage sites","volume":"392","author":"O Schilling","year":"2011","journal-title":"Biol Chem"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"D227","DOI":"10.1093\/nar\/gkp971","article-title":"MEROPS: the peptidase database","volume":"38","author":"ND Rawlings","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"D343","DOI":"10.1093\/nar\/gkr987","article-title":"MEROPS: the database of proteolytic enzymes, their substrates and inhibitors","volume":"40","author":"ND Rawlings","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"3415","DOI":"10.1093\/bioinformatics\/btr594","article-title":"Cascade detection for the extraction of localized sequence features; specificity results for HIV-1 protease and structure-function results for the Schellman loop","volume":"27","author":"NE Newell","year":"2011","journal-title":"Bioinformatics"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"6097","DOI":"10.1093\/nar\/18.20.6097","article-title":"Sequence logos: a new way to display consensus sequences","volume":"20","author":"TD Schneider","year":"1990","journal-title":"Nucleic Acids Res"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/nmeth1109-786","article-title":"Improved visualization of protein consensus sequences by iceLogo","volume":"11","author":"N Colaert","year":"2009","journal-title":"Nat Methods"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1002\/j.1538-7305.1948.tb01338.x","article-title":"A Mathematical Theory of Communication","volume":"3","author":"CE Shannon","year":"1948","journal-title":"Bell System Technical J"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1103\/PhysRev.106.620","article-title":"Information theory and statistical mechanics","volume":"4","author":"ET Jaynes","year":"1957","journal-title":"Phys Rev"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/0022-2836(86)90165-8","article-title":"Information Content of Binding Sites on Nucleotide Sequences","volume":"188","author":"TD Schneider","year":"1986","journal-title":"J Mol Biol"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1124\/dmd.110.034645","article-title":"Quantifying and predicting the Promiscuity and Isoform Specificity of Small-Molecule Cytochrome P450 Inhibitors","volume":"38","author":"A Nath","year":"2010","journal-title":"Drug Metab Dispos"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1021\/bi701448p","article-title":"A Quantitative Index of Substrate Promiscuity","volume":"47","author":"A Nath","year":"2008","journal-title":"Biochemistry"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1093\/bib\/bbr059","article-title":"A review of statistical methods for prediction of proteolytic cleavage","volume":"3","author":"DA DuVerle","year":"2012","journal-title":"Brief Bioinform"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"D546","DOI":"10.1093\/nar\/gkl813","article-title":"CutDB: a proteolytic event database","volume":"35","author":"Y Igarashi","year":"2007","journal-title":"Nucleic Acids Res"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"D611","DOI":"10.1093\/nar\/gkn683","article-title":"PMAP: databases for analyzing proteolytic events and pathways","volume":"37","author":"Y Igarashi","year":"2009","journal-title":"Nucleic Acids Res"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1002\/prot.340040204","article-title":"Oligopeptide Biases in Protein Sequences and Their Use in Predicting Protein Coding Regions in Nucleotide-Sequences","volume":"2","author":"P McCaldon","year":"1988","journal-title":"Proteins"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"8967","DOI":"10.1021\/bi00152a037","article-title":"Interdependency of the Binding Subsites in Subtilisin","volume":"31","author":"H Gron","year":"1992","journal-title":"Biochemistry"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1515\/BC.2009.065","article-title":"Subsite cooperativity in protease specificity","volume":"390","author":"NM Ng","year":"2009","journal-title":"Biol Chem"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"D71","DOI":"10.1093\/nar\/gkr981","article-title":"Reorganizing the protein space at the Universal Protein Resource (UniProt)","volume":"40","year":"2012","journal-title":"Nucleic Acid Res"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"2947","DOI":"10.1093\/bioinformatics\/btm404","article-title":"Clustal W and Clustal X version 2.0","volume":"21","author":"MA Larkin","year":"2007","journal-title":"Bioinformatics"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/S0168-9525(00)02024-2","article-title":"EMBOSS: The European Molecular Biology Open Software Suite","volume":"6","author":"P Rice","year":"2000","journal-title":"Trends Genet"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1126\/science.155.3760.279","article-title":"Construction of phylogenetic trees","volume":"3760","author":"WM Fitch","year":"1967","journal-title":"Science"},{"issue":"(Suppl 2)","key":"ref51","doi-asserted-by":"crossref","first-page":"W475","DOI":"10.1093\/nar\/gkr201","article-title":"Interactive Tree of Life v2: online annotation and display of phylogenetic trees made easy","volume":"39","author":"I Letunic","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"ref52","unstructured":"DeLano WL (2008) The Pymol Molecular Graphics System. <comment>Available: <ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/pymol.org\" xlink:type=\"simple\">http:\/\/pymol.org<\/ext-link><\/comment>"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0969-2126(00)00551-7","article-title":"Structural Basis for Inhibition Promiscuity of Dual Specific Thrombin and Factor Xa Blood Coagulation Inhibitors","volume":"9","author":"H Nar","year":"2001","journal-title":"Structure"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1002\/pro.5560010402","article-title":"The refined 1.9-A X-ray crystal structure of D-Phe-Pro-Arg chloromethylketone-inhibited human a-thrombin: Structure analysis, overall structure, electrostatic properties, detailed active-site geometry, and structure-function relationships","volume":"1","author":"W Bode","year":"1992","journal-title":"Protein Sci"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1073\/pnas.86.5.1434","article-title":"Yeast prohormone processing enzyme (KEX2 gene product) is a Ca<sup>2+<\/sup>-dependent serine protease","volume":"86","author":"RS Fuller","year":"1989","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref56","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1111\/j.1538-7836.2005.01456.x","article-title":"Determinants of specificity in coagulation proteases","volume":"3","author":"MJ Page","year":"2005","journal-title":"J Thromb Haemost"},{"key":"ref57","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1038\/nsb941","article-title":"The crystal structure of the preprotein processing proteinase furin explains its stringent specificity","volume":"7","author":"S Henrich","year":"2003","journal-title":"Nat Struct Biol"},{"key":"ref58","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1385\/MB:22:1:051","article-title":"Molecular Determinants of Metalloproteinase Substrate Specificity","volume":"22","author":"CM Overall","year":"2002","journal-title":"Mol Biotechnol"},{"key":"ref59","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.drudis.2007.06.003","article-title":"Insight into the structural determinants for selective inhibition of matrix metalloproteinases","volume":"15\u201316","author":"B Pirard","year":"2007","journal-title":"Drug Discov Today"},{"key":"ref60","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1161\/01.RES.0000070112.80711.3D","article-title":"Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases: Structure, Function, and Biochemistry","volume":"92","author":"R Visse","year":"2003","journal-title":"Circ Res"},{"key":"ref61","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/90273","article-title":"Determination of protease cleavage site motifs using mixture-based oriented peptide libraries","volume":"19","author":"BE Turk","year":"2001","journal-title":"Nat Biotechnol"},{"key":"ref62","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1074\/mcp.M000032-MCP201","article-title":"A Statistics-based Platform for Quantitative N-terminome Analysis and Identification of Protease Cleavage Products","volume":"5","author":"U Auf dem Keller","year":"2010","journal-title":"Mol Cell Proteomics"},{"key":"ref63","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1126\/science.281.5381.1312","article-title":"Caspases: Enemies Within","volume":"281","author":"NA Thornberry","year":"1998","journal-title":"Science"},{"key":"ref64","doi-asserted-by":"crossref","first-page":"17907","DOI":"10.1074\/jbc.272.29.17907","article-title":"A Combinatorial Approach Defines Specifities of Members of the Caspase Family and Granzyme B","volume":"29","author":"NA Thornberry","year":"1997","journal-title":"J Biol Chem"},{"key":"ref65","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/S0166-2236(99)01479-4","article-title":"Calpain and caspase: can you tell the difference?","volume":"2","author":"KKW Wang","year":"2000","journal-title":"Trends Neurosci"},{"key":"ref66","doi-asserted-by":"crossref","first-page":"12824","DOI":"10.1074\/jbc.M513331200","article-title":"Substrate Profiling of Cysteine Proteases Using a Combinatorial Peptide Library Identifies Functionally Unique Specificities","volume":"18","author":"Y Choe","year":"2006","journal-title":"J Biol Chem"},{"key":"ref67","first-page":"4549","article-title":"Chem Rev","volume":"102","author":"M Paetzel","year":"2002","journal-title":"Chem Rev"},{"issue":"(Suppl I)","key":"ref68","doi-asserted-by":"crossref","first-page":"S15","DOI":"10.1186\/1471-2105-9-S1-S15","article-title":"Modeling Escherichia coli signal peptidase complex with bound substrate: determinants in the mature peptide influencing signal peptide cleavage","volume":"9","author":"KH Choo","year":"2008","journal-title":"BMC Bioinformatics"},{"key":"ref69","doi-asserted-by":"crossref","first-page":"3417","DOI":"10.1016\/S0021-9258(19)39783-2","article-title":"Maturation of Escherichia coli Maltose-binding Protein by Signal Peptidase I in Vivo","volume":"6","author":"JD Fikes","year":"1990","journal-title":"J Biol Chem"},{"key":"ref70","unstructured":"Dunn BM, Rao M (2004) Human immunodeficiency virus 1 retropepsin. In: Barrett AJ, Rawlings ND, Woessner JF, editors. Handbook of Proteolytic Enzymes, 2 ed. pp.144\u2013154."},{"key":"ref71","unstructured":"Van Den Burg B, Eijsink V (2004) Thermolysin and related <italic>Bacillus<\/italic> metallopeptidases. In: Barrett AJ, Rawlings ND, Woessner JF, editors. Handbook of Proteolytic Enzymes, 2 ed. pp. 374\u2013387."},{"key":"ref72","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1042\/bj1080893","article-title":"The Use of Thermolysin in Amino Acid Sequence Determination","volume":"108","author":"RP Ambler","year":"1968","journal-title":"Biochem J"},{"key":"ref73","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/S0168-1656(03)00024-5","article-title":"Synthesis of ZAlaPheOMe, the precursor of bitter dipeptide in the two-phase ethyl acetate\/water system catalysed by thermolysin","volume":"102","author":"A Trusek-Holownia","year":"2003","journal-title":"J Biotechnol"},{"key":"ref74","doi-asserted-by":"crossref","first-page":"11274","DOI":"10.1016\/S0021-9258(18)67379-X","article-title":"Purification and Characterization of a Novel Neurotensin-degrading Peptidase from Rat Brain Synaptic Membranes","volume":"24","author":"F Checler","year":"1986","journal-title":"J Biol Chem"},{"key":"ref75","doi-asserted-by":"crossref","first-page":"24448","DOI":"10.1074\/jbc.M801252200","article-title":"Intracellular Peptides as Natural Regulators of Cell Signalling","volume":"36","author":"FM Cunha","year":"2008","journal-title":"J Biol Chem"},{"key":"ref76","doi-asserted-by":"crossref","first-page":"9677","DOI":"10.1074\/jbc.272.15.9677","article-title":"Substrate Specificities of Caspase Family Proteases","volume":"15","author":"RV Talanian","year":"1997","journal-title":"J Biol Chem"},{"key":"ref77","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1111\/j.1462-5822.2008.01176.x","article-title":"Malarial proteases and host cell egress: an \u2018emerging\u2019 cascade","volume":"10","author":"MJ Blackman","year":"2008","journal-title":"Cell Microbiol"},{"key":"ref78","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/S1097-2765(03)00308-3","article-title":"A Despecialization Step Underlying Evolution of a Family of Serine Proteases","volume":"12","author":"MA Wouters","year":"2010","journal-title":"Mol Cell"},{"key":"ref79","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1038\/nrd3053","article-title":"Emerging principles in protease-based drug discovery","volume":"9","author":"M Drag","year":"2010","journal-title":"Nat Rev Drug Discov"},{"key":"ref80","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1016\/j.biochi.2010.07.017","article-title":"Third generation of matrix metalloprotease inhibitors: gain in selectivity by targeting the depth of the S<sub>1<\/sub>\u2032 cavity","volume":"92","author":"L Devel","year":"2010","journal-title":"Biochimie"},{"key":"ref81","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1126\/science.6369538","article-title":"Evolution of Proteolytic Enzymes","volume":"4647","author":"H Neurath","year":"1984","journal-title":"Science"},{"key":"ref82","doi-asserted-by":"crossref","first-page":"10330","DOI":"10.1021\/ja909908y","article-title":"Backbone Flexibility Controls the Activity and Specificity of a Protein-Protein Interface: Specificity in Snake Venom Metalloproteases","volume":"132","author":"HG Wallnoefer","year":"2010","journal-title":"J Am Chem Soc"},{"key":"ref83","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.cbpa.2009.11.028","article-title":"What makes an enzyme promiscuous?","volume":"2","author":"A Babtie","year":"2010","journal-title":"Curr Opin Chem Biol"},{"key":"ref84","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/nchembio0508-270","article-title":"Engineering protease specificity made simple, but not simpler","volume":"5","author":"E Di Cera","year":"2008","journal-title":"Nat Chem Biol"},{"key":"ref85","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/nrm858","article-title":"Protease degradomics: a new challenge for proteomics","volume":"3","author":"C Lopez-Otin","year":"2002","journal-title":"Nat Rev Mol Cell Biol"}],"container-title":["PLoS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pcbi.1003007","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,9]],"date-time":"2024-05-09T07:27:19Z","timestamp":1715239639000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1003007"}},"subtitle":[],"editor":[{"given":"James M.","family":"Briggs","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2013,4,18]]},"references-count":85,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2013,4,18]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1003007","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,4,18]]}}}