{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T07:38:10Z","timestamp":1774424290640,"version":"3.50.1"},"reference-count":62,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2014,2,6]],"date-time":"2014-02-06T00:00:00Z","timestamp":1391644800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"DOI":"10.1371\/journal.pcbi.1003394","type":"journal-article","created":{"date-parts":[[2014,2,6]],"date-time":"2014-02-06T21:46:55Z","timestamp":1391723215000},"page":"e1003394","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":382,"title":["A Unified View of \u201cHow Allostery Works\u201d"],"prefix":"10.1371","volume":"10","author":[{"given":"Chung-Jung","family":"Tsai","sequence":"first","affiliation":[]},{"given":"Ruth","family":"Nussinov","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2014,2,6]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.cell.2013.03.034","article-title":"Allostery in disease and in drug discovery","volume":"153","author":"R Nussinov","year":"2013","journal-title":"Cell"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.molcel.2011.03.004","article-title":"Catalytic control in the EGF receptor and its connection to general kinase regulatory mechanisms","volume":"42","author":"N Jura","year":"2011","journal-title":"Mol Cell"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/376313a0","article-title":"Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex","volume":"376","author":"PD Jeffrey","year":"1995","journal-title":"Nature"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1016\/j.jmb.2012.12.019","article-title":"Three sites and you are out: ternary synergistic allostery controls aromatic amino acid biosynthesis in mycobacterium tuberculosis","volume":"425","author":"NJ Blackmore","year":"2013","journal-title":"J Mol Biol"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1016\/j.jmb.2007.08.059","article-title":"Predicting allosteric communication in myosin via a pathway of conserved residues","volume":"373","author":"S Tang","year":"2007","journal-title":"J Mol Biol"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/nchembio.1214","article-title":"Ligand-binding dynamics rewire cellular signaling via estrogen receptor-alpha","volume":"9","author":"S Srinivasan","year":"2013","journal-title":"Nat Chem Biol"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1038\/nchembio.451","article-title":"Coupling of receptor conformation and ligand orientation determine graded activity","volume":"6","author":"JB Bruning","year":"2010","journal-title":"Nat Chem Biol"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.cell.2009.11.022","article-title":"Transient non-native hydrogen bonds promote activation of a signaling protein","volume":"139","author":"AK Gardino","year":"2009","journal-title":"Cell"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1126\/science.291.5512.2429","article-title":"Two-state allosteric behavior in a single-domain signaling protein","volume":"291","author":"BF Volkman","year":"2001","journal-title":"Science"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1126\/science.1749933","article-title":"The energy landscapes and motions of proteins","volume":"254","author":"H Frauenfelder","year":"1991","journal-title":"Science"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.tibs.2008.05.009","article-title":"Allostery: an illustrated definition for the \u2018second secret of life\u2019","volume":"33","author":"AW Fenton","year":"2008","journal-title":"Trends Biochem Sci"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/S0022-2836(63)80091-1","article-title":"Allosteric proteins and cellular control systems","volume":"6","author":"J Monod","year":"1963","journal-title":"J Mol Biol"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1146\/annurev-biophys-050511-102222","article-title":"Allostery and the Monod-Wyman-Changeux model after 50 years","volume":"41","author":"J-P Changeux","year":"2012","journal-title":"Annu Rev Biophys"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1146\/annurev-biophys-050511-102319","article-title":"Structural and energetic basis of allostery","volume":"41","author":"VJ Hilser","year":"2012","journal-title":"Annu Rev Biophys"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1110\/ps.03259908","article-title":"Allostery and cooperativity revisited","volume":"17","author":"Q Cui","year":"2008","journal-title":"Protein Sci"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"6056","DOI":"10.1073\/pnas.1102376108","article-title":"Turning a protein kinase on or off from a single allosteric site via disulfide trapping","volume":"108","author":"JD Sadowsky","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"4134","DOI":"10.1073\/pnas.1120519109","article-title":"Agonism\/antagonism switching in allosteric ensembles","volume":"109","author":"HN Motlagh","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"8502","DOI":"10.1073\/pnas.95.15.8502","article-title":"The allosteric mechanism of the chaperonin GroEL: A dynamic analysis","volume":"95","author":"JP Ma","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.jmb.2005.10.064","article-title":"The allosteric mechanism of yeast chorismate mutase: a dynamic analysis","volume":"356","author":"YF Kong","year":"2006","journal-title":"J Mol Biol"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"e1000129","DOI":"10.1371\/journal.pcbi.1000129","article-title":"Allosteric communication in myosin V: from small conformational changes to large directed movements","volume":"4","author":"M Cecchini","year":"2008","journal-title":"PLoS Comput Biol"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/S0022-2836(65)80285-6","article-title":"On the nature of allosteric transitions: a plausible model","volume":"12","author":"J Monod","year":"1965","journal-title":"J Mol Biol"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1038\/228726a0","article-title":"Stereochemistry of cooperative effects in haemoglobin","volume":"228","author":"MF Perutz","year":"1970","journal-title":"Nature"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/0022-2836(72)90077-0","article-title":"A mathematical model for structure-function relations in hemoglobin","volume":"72","author":"A Szabo","year":"1972","journal-title":"J Mol Biol"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1080\/15216540701272380","article-title":"Evolution of allosteric models for hemoglobin","volume":"59","author":"WA Eaton","year":"2007","journal-title":"IUBMB Life"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1002\/iub.6","article-title":"Cooperativity and allostery in haemoglobin function","volume":"60","author":"C Ciaccio","year":"2008","journal-title":"IUBMB Life"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1016\/j.bbapap.2008.04.025","article-title":"Protein dynamics explain the allosteric behaviors of hemoglobin","volume":"1784","author":"T Yonetani","year":"2008","journal-title":"Biochim Biophys Acta"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1002\/prot.20232","article-title":"Is allostery an intrinsic property of all dynamic proteins?","volume":"57","author":"K Gunasekaran","year":"2004","journal-title":"Proteins"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1002\/prot.1107","article-title":"Structured disorder and conformational selection","volume":"44","author":"CJ Tsai","year":"2001","journal-title":"Proteins"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1110\/ps.9.1.10","article-title":"Folding and binding cascades: Dynamic landscapes and population shifts","volume":"9","author":"S Kumar","year":"2000","journal-title":"Protein Sci"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"125102","DOI":"10.1063\/1.3565025","article-title":"Statistical mechanics of protein allostery: roles of backbone and side-chain structural fluctuations","volume":"134","author":"K Itoh","year":"2011","journal-title":"J Chem Phys"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/j.tips.2007.06.004","article-title":"Allosteric GPCR modulators: taking advantage of permissive receptor pharmacology","volume":"28","author":"K Leach","year":"2007","journal-title":"Trends Pharmacol Sci"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1124\/jpet.105.090886","article-title":"Analysis of allosterism in functional assays","volume":"315","author":"FJ Ehlert","year":"2005","journal-title":"J Pharmacol Exp Ther"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.tips.2009.06.007","article-title":"'7TM receptor allostery: putting numbers to shapeshifting proteins","volume":"30","author":"TP Kenakin","year":"2009","journal-title":"Trends Pharmacol Sci"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1124\/mol.105.016162","article-title":"Allosteric modulation of the cannabinoid CB1 receptor","volume":"68","author":"MR Price","year":"2005","journal-title":"Mol Pharmacol"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev.pharmtox.47.120505.105159","article-title":"Allosteric modulation of G protein-coupled receptors","volume":"47","author":"LT May","year":"2007","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0165-6147(00)88989-0","article-title":"The two-state model of receptor activation","volume":"16","author":"P Leff","year":"1995","journal-title":"Trends Pharmacol Sci"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1110\/ps.8.6.1181","article-title":"Folding funnels, binding funnels, and protein function","volume":"8","author":"CJ Tsai","year":"1999","journal-title":"Protein Sci"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1152\/physiol.00002.2010","article-title":"Energy landscapes as a tool to integrate GPCR structure, dynamics, and function","volume":"25","author":"X Deupi","year":"2010","journal-title":"Physiology"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"9517","DOI":"10.1073\/pnas.161239298","article-title":"Propagating conformational changes over long (and short) distances in proteins","volume":"98","author":"EW Yu","year":"2001","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref40","doi-asserted-by":"crossref","unstructured":"Gardino AK, Kern D (2007) Functional dynamics of response regulators using NMR relaxation techniques. In: Simon MI, Crane BR, Crane A, editors. Two-component signaling systems, Pt B. pp. 149\u2013165.","DOI":"10.1016\/S0076-6879(07)23006-X"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/S0076-6879(01)39315-1","article-title":"Nuclear magnetic resonance methods for quantifying microsecond-to-millisecond motions in biological macromolecules","volume":"339","author":"AG Palmer","year":"2001","journal-title":"Methods Enzymol"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.abb.2011.10.023","article-title":"NMR insights into protein allostery","volume":"519","author":"G Manley","year":"2012","journal-title":"Arch Biochem Biophys"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1016\/j.str.2009.06.008","article-title":"The origin of allosteric functional modulation: multiple pre-existing pathways","volume":"17","author":"A del Sol","year":"2009","journal-title":"Structure"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/nsb881","article-title":"Evolutionarily conserved networks of residues mediate allosteric communication in proteins","volume":"10","author":"GM Suel","year":"2003","journal-title":"Nat Struct Biol"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"e1002661","DOI":"10.1371\/journal.pcbi.1002661","article-title":"Allosteric communication across the native and mutated KIT receptor tyrosine kinase","volume":"8","author":"E Laine","year":"2012","journal-title":"PLoS Comput Biol"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.jmb.2012.11.041","article-title":"Impact of mutations on the allosteric conformational equilibrium","volume":"425","author":"P Weinkam","year":"2013","journal-title":"J Mol Biol"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"e1002179","DOI":"10.1371\/journal.pcbi.1002179","article-title":"Computational modeling of allosteric communication reveals organizing principles of mutation-induced signaling in ABL and EGFR kinases","volume":"7","author":"A Dixit","year":"2011","journal-title":"PLoS Comput Biol"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"W249","DOI":"10.1093\/nar\/gkt284","article-title":"MCPath: Monte Carlo path generation approach to predict likely allosteric pathways and functional residues","volume":"41","author":"C Kaya","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"7787","DOI":"10.1073\/pnas.0914877107","article-title":"Evolution-guided discovery and recoding of allosteric pathway specificity determinants in psychoactive bioamine receptors","volume":"107","author":"GJ Rodriguez","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"5608","DOI":"10.1073\/pnas.1011995108","article-title":"Unsuspected pathway of the allosteric transition in hemoglobin","volume":"108","author":"S Fischer","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"3052","DOI":"10.1529\/biophysj.106.099440","article-title":"Screened nonbonded interactions in native proteins manipulate optimal paths for robust residue communication","volume":"92","author":"AR Atilgan","year":"2007","journal-title":"Biophys J"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"e1002301","DOI":"10.1371\/journal.pcbi.1002301","article-title":"Coherent conformational degrees of freedom as a structural basis for allosteric communication","volume":"7","author":"S Mitternacht","year":"2011","journal-title":"PLoS Comput Biol"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"6133","DOI":"10.1073\/pnas.1017311108","article-title":"Mapping allostery through the covariance analysis of NMR chemical shifts","volume":"108","author":"R Selvaratnam","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1124\/pr.55.4.4","article-title":"International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on terms and symbols in quantitative pharmacology","volume":"55","author":"RR Neubig","year":"2003","journal-title":"Pharmacol Rev"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1073\/pnas.0707401105","article-title":"Allosteric effects in the marginally stable von Hippel-Lindau tumor suppressor protein and allostery-based rescue mutant design","volume":"105","author":"J Liu","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref56","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1146\/annurev.pharmtox.010909.105800","article-title":"Molecular mechanism of beta-arrestin-biased agonism at seven-transmembrane receptors","volume":"52","author":"E Reiter","year":"2012","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"ref57","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1016\/0006-2952(83)90679-2","article-title":"An allosteric model for benzodiazepine receptor function","volume":"32","author":"FJ Ehlert","year":"1983","journal-title":"Biochem Pharmacol"},{"key":"ref58","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1038\/nrd746","article-title":"Allosteric binding sites on cell-surface receptors: novel targets for drug discovery","volume":"1","author":"A Christopoulos","year":"2002","journal-title":"Nat Revi Drug Discove"},{"key":"ref59","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/S0026-895X(25)14327-7","article-title":"Modification of the binding properties of muscarinic receptors by gallamine","volume":"23","author":"JM Stockton","year":"1983","journal-title":"Mol Pharmacol"},{"key":"ref60","doi-asserted-by":"crossref","first-page":"30567","DOI":"10.1074\/jbc.M110.111856","article-title":"Synergistic allostery, a sophisticated regulatory network for the control of aromatic amino acid biosynthesis in mycobacterium tuberculosis","volume":"285","author":"CJ Webby","year":"2010","journal-title":"J Biol Chem"},{"key":"ref61","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1124\/mol.58.6.1412","article-title":"Modeling the functional effects of allosteric modulators at pharmacological receptors: an extension of the two-state model of receptor activation","volume":"58","author":"DA Hall","year":"2000","journal-title":"Mol Pharmacol"},{"key":"ref62","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1124\/jpet.108.136960","article-title":"Two-state models and the analysis of the allosteric effect of gallamine at the M-2 muscarinic receptor","volume":"325","author":"FJ Ehlert","year":"2008","journal-title":"J Pharmacol Exp Ther"}],"container-title":["PLoS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pcbi.1003394","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T20:07:47Z","timestamp":1746130067000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1003394"}},"subtitle":[],"editor":[{"given":"Dennis R.","family":"Livesay","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2014,2,6]]},"references-count":62,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2014,2,6]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1003394","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,2,6]]}}}