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Characteristics of Allosteric Proteins, Sites, and Modulators

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Protein Allostery in Drug Discovery

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1163))

Abstract

Allostery is considered one of the most direct and efficient ways to regulate biological macromolecule functions. Allostery is increasingly receiving attention in the field of drug discovery because of the unique advantages of allosteric modulators such as high selectivity and low toxicity. Because of technical breakthroughs in the allosteric studies, the understanding of the characteristics of allosteric entities such as allosteric proteins and their allosteric sites and modulators has made great strides. These features play a critical role in both the evolution of the allosteric concept and the prediction of allosteric interactions. In this chapter, we highlight the fundamental characteristics of allosteric proteins, allosteric sites, and allosteric modulators. Importantly, the applications of such principles in real cases are depicted in detail. Collectively, these characteristics are beneficial in aiding allosteric drug design and allosteric mechanism research.

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References

  1. Araújo-Bazán L, Ruiz-Avila LB, Andreu D, Huecas S, Andreu JM (2016) Cytological profile of antibacterial FtsZ inhibitors and synthetic peptide MciZ. Front Microbiol 7:1558

    Article  PubMed  PubMed Central  Google Scholar 

  2. Artola M, Ruíz-Avila LB, Ramírez-Aportela E, Martínez RF, Araujo-Bazán L, Vázquez-Villa H, Martín-Fontecha M, Oliva MA, Martín-Galiano AJ, Chacón P (2017) The structural assembly switch of cell division protein FtsZ probed with fluorescent allosteric inhibitors. Chem Sci 8:1525–1534

    Article  CAS  PubMed  Google Scholar 

  3. Babel H, Bischofs IB (2016) Molecular and cellular factors control signal transduction via switchable allosteric modulator proteins (SAMPs). BMC Syst Biol 10:35

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Badireddy S, Yunfeng G, Ritchie M, Akamine P, Wu J, Kim CW, Taylor SS, Qingsong L, Swaminathan K, Anand GS (2010) Cyclic AMP analog blocks kinase activation by stabilizing inactive conformation: conformational selection highlights a new concept in allosteric inhibitor design. Mol Cell Proteomics 10. https://doi.org/10.1074/mcp.M110.004390

    Article  CAS  Google Scholar 

  5. Bai X, Yan C, Yang G, Lu P, Ma D, Sun L, Zhou R, Scheres SHW, Shi Y (2015) An atomic structure of human γ-secretase. Nature 525:212–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Banerjee S, Bartesaghi A, Merk A, Rao P, Bulfer SL, Yan Y, Green N, Mroczkowski B, Neitz RJ, Wipf P (2016) 2.3 Å resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition. Science 351:871–875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Berezin C, Glaser F, Rosenberg J, Paz I, Pupko T, Fariselli P, Casadio R, Ben-Tal N (2004) ConSeq: the identification of functionally and structurally important residues in protein sequences. Bioinformatics 20:1322–1324

    Article  CAS  PubMed  Google Scholar 

  8. Bessa LM, Launay H, Dujardin M, Cantrelle F-X, Lippens G, Landrieu I, Schneider R, Hanoulle X (2017) NMR reveals the intrinsically disordered domain 2 of NS5A protein as an allosteric regulator of the hepatitis C virus RNA polymerase NS5B. J Biol Chem 292:18024–18043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Betzi S, Alam R, Martin M, Lubbers DJ, Han H, Jakkaraj SR, Georg GI, Schönbrunn E (2011) Discovery of a potential allosteric ligand binding site in CDK2. ACS Chem Biol 6:492–501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bian Z-M, Elner SG, Khanna H, Murga-Zamalloa CA, Patil S, Elner VM (2011) Expression and functional roles of caspase-5 in inflammatory responses of human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 52:8646–8656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411:355–365

    Article  CAS  PubMed  Google Scholar 

  12. Bock A, Schrage R, Mohr K (2018) Allosteric modulators targeting CNS muscarinic receptors. Neuropharmacology 136:427–437

    Article  CAS  PubMed  Google Scholar 

  13. Bonomi M, Pellarin R, Vendruscolo M (2018) Simultaneous determination of protein structure and dynamics using cryo-electron microscopy. Biophys J 114:1604–1613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Boulton S, Melacini G (2016) Advances in NMR methods to map allosteric sites: from models to translation. Chem Rev 116:6267–6304

    Article  CAS  PubMed  Google Scholar 

  15. Bowman GR, Bolin ER, Hart KM, Maguire BC, Marqusee S (2015) Discovery of multiple hidden allosteric sites by combining Markov state models and experiments. Proc Natl Acad Sci U S A 112:2734–2739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Brignole EJ, Tsai K-L, Chittuluru J, Li H, Aye Y, Penczek PA, Stubbe J, Drennan CL, Asturias F (2018) 3.3-Å resolution cryo-EM structure of human ribonucleotide reductase with substrate and allosteric regulators bound. Elife 7:e31502

    Article  PubMed  PubMed Central  Google Scholar 

  17. Bryant C, Fitzgerald KA (2009) Molecular mechanisms involved in inflammasome activation. Trends Cell Biol 19:455–464

    Article  CAS  PubMed  Google Scholar 

  18. Buzko O, Shokat KM (2002) A kinase sequence database: sequence alignments and family assignment. Bioinformatics 18:1274–1275

    Article  CAS  PubMed  Google Scholar 

  19. Campitelli P, Guo J, Zhou H-X, Ozkan SB (2018) Hinge-shift mechanism modulates allosteric regulations in human pin1. J Phys Chem B 122:5623–5629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Capdevila DA, Braymer JJ, Edmonds KA, Wu H, Giedroc DP (2017) Entropy redistribution controls allostery in a metalloregulatory protein. Proc Natl Acad Sci U S A 114:4424–4429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Celniker G, Nimrod G, Ashkenazy H, Glaser F, Martz E, Mayrose I, Pupko T, Ben-Tal N (2013) ConSurf: using evolutionary data to raise testable hypotheses about protein function. Isr J Chem 53:199–206

    Article  CAS  Google Scholar 

  22. Chandramohan A, Krishnamurthy S, Larsson A, Nordlund P, Jansson A, Anand GS (2016) Predicting allosteric effects from orthosteric binding in Hsp90-ligand interactions: implications for fragment-based drug design. PLoS Comput Biol 12:e1004840

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Changeux J-P (2010) Allosteric receptors: from electric organ to cognition. Annu Rev Pharmacol Toxicol 50:1–38

    Article  CAS  PubMed  Google Scholar 

  24. Changeux J-P (2012) Allostery and the Monod-Wyman-Changeux model after 50 years. Annu Rev Biophys 41:103–133

    Article  CAS  PubMed  Google Scholar 

  25. Changeux J-P (2013) 50 years of allosteric interactions: the twists and turns of the models. Nat Rev Mol cell Biol 14:819–829

    Article  CAS  PubMed  Google Scholar 

  26. Chen I (2013) Allostery through DNA. Nat Struct & Mol Biol 20:410

    Google Scholar 

  27. Chen H, Marsiglia WM, Cho M-K, Huang Z, Deng J, Blais SP, Gai W, Bhattacharya S, Neubert TA, Traaseth NJ (2017) Elucidation of a four-site allosteric network in fibroblast growth factor receptor tyrosine kinases. Elife 6:e21137

    Google Scholar 

  28. Cheng RKY, Fiez-Vandal C, Schlenker O, Edman K, Aggeler B, Brown DG, Brown GA, Cooke RM, Dumelin CE, Doré AS, Geschwindner S, Grebner C, Hermansson N-O, Jazayeri A, Johansson P, Leong L, Prihandoko R, Rappas M, Soutter H, Snijder A, Sundström L, Tehan B, Thornton P, Troast D, Wiggin G, Zhukov A, Marshall FH, Dekker N (2017) Structural insight into allosteric modulation of protease-activated receptor 2. Nature 545:112–115

    Article  CAS  PubMed  Google Scholar 

  29. Chodera JD, Noé F (2014) Markov state models of biomolecular conformational dynamics. Curr Opin Struct Biol 25:135–144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Christopoulos A (2002) Allosteric binding sites on cell-surface receptors: novel targets for drug discovery. Nat Rev Drug Discov 1:198–210

    Article  CAS  PubMed  Google Scholar 

  31. Coleman JA, Green EM, Gouaux E (2016) X-ray structures and mechanism of the human serotonin transporter. Nature 532:334–339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Collier G, Ortiz V (2013) Emerging computational approaches for the study of protein allostery. Arch Biochem Biophys 538:6–15

    Article  CAS  PubMed  Google Scholar 

  33. Cong X, Liu Y, Liu W, Liang X, Laganowsky A (2017) Allosteric modulation of protein-protein interactions by individual lipid binding events. Nat Commun 8:2203

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Congreve M, Oswald C, Marshall FH (2017) Applying structure-based drug design approaches to allosteric modulators of GPCRs. Trends Pharmacol Sci 38:837–847

    Article  CAS  PubMed  Google Scholar 

  35. Conn PJ, Christopoulos A, Lindsley CW (2009a) Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov 8:41–54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Conn PJ, Jones CK, Lindsley CW (2009b) Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders. Trends Pharmacol Sci 30:148–155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Conn PJ, Lindsley CW, Meiler J, Niswender CM (2014) Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders. Nat Rev Drug Discov 13:692–708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Csermely P, Korcsmáros T, Kiss HJM, London G, Nussinov R (2013) Structure and dynamics of molecular networks: a novel paradigm of drug discovery: a comprehensive review. Pharmacol Ther 138:333–408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Csizmok V, Orlicky S, Cheng J, Song J, Bah A, Delgoshaie N, Lin H, Mittag T, Sicheri F, Chan HS, Tyers M, Forman-Kay JD (2017) An allosteric conduit facilitates dynamic multisite substrate recognition by the SCFCdc4 ubiquitin ligase. Nat Commun 8:13943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Das D, Krantz BA (2016) Peptide- and proton-driven allosteric clamps catalyze anthrax toxin translocation across membranes. Proc Natl Acad Sci U S A 113:9611–9616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. De Cesco S, Kurian J, Dufresne C, Mittermaier AK, Moitessier N (2017) Covalent inhibitors design and discovery. Eur J Med Chem 138:96–114

    Article  PubMed  CAS  Google Scholar 

  42. Demerdash ONA, Daily MD, Mitchell JC (2009) Structure-based predictive models for allosteric hot spots. PLoS Comput Biol 5:e1000531

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Di Russo NV, Martí MA, Roitberg AE (2014) Underlying thermodynamics of ph-dependent allostery. J Phys Chem B 118:12818–12826. https://doi.org/10.1021/jp507971v

    Article  CAS  PubMed  Google Scholar 

  44. Digby GJ, Noetzel MJ, Bubser M, Utley TJ, Walker AG, Byun NE, Lebois EP, Xiang Z, Sheffler DJ, Cho HP (2012) Novel allosteric agonists of M1 muscarinic acetylcholine receptors induce brain region-specific responses that correspond with behavioral effects in animal models. J Neurosci 32:8532–8544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dokholyan NV (2016) Controlling Allosteric Networks in Proteins. Chem Rev 116:6463–6487

    Article  CAS  PubMed  Google Scholar 

  46. Doré AS, Okrasa K, Patel JC, Serrano-Vega M, Bennett K, Cooke RM, Errey JC, Jazayeri A, Khan S, Tehan B (2014) Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. Nature 511:557–561

    Article  PubMed  CAS  Google Scholar 

  47. Dror RO, Pan AC, Arlow DH, Borhani DW, Maragakis P, Shan Y, Xu H, Shaw DE (2011) Pathway and mechanism of drug binding to G-protein-coupled receptors. Proc Natl Acad Sci U S A 108:13118–13123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Dror RO, Green HF, Valant C, Borhani DW, Valcourt JR, Pan AC, Arlow DH, Canals M, Lane JR, Rahmani R, Baell JB, Sexton PM, Christopoulos A, Shaw DE (2013) Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs. Nature 503:295–299

    Article  CAS  PubMed  Google Scholar 

  49. Eddy MT, Lee M-Y, Gao Z-G, White KL, Didenko T, Horst R, Audet M, Stanczak P, McClary KM, Han GW, Jacobson KA, Stevens RC, Wüthrich K (2018) Allosteric coupling of drug binding and intracellular signaling in the A2A adenosine receptor. Cell 172:68–80.e12. https://doi.org/10.1016/j.cell.2017.12.004

    Article  CAS  PubMed  Google Scholar 

  50. Elsen NL, Lu J, Parthasarathy G, Reid JC, Sharma S, Soisson SM, Lumb KJ (2012) Mechanism of action of the cell-division inhibitor PC190723: modulation of FtsZ assembly cooperativity. J Am Chem Soc 134:12342–12345

    Article  CAS  PubMed  Google Scholar 

  51. Engers DW, Lindsley CW (2013) Allosteric modulation of Class C GPCRs: a novel approach for the treatment of CNS disorders. Drug Discov Today Technol 10:e269–e276

    Article  PubMed  Google Scholar 

  52. Fang Z, Grütter C, Rauh D (2012) Strategies for the selective regulation of kinases with allosteric modulators: exploiting exclusive structural features. ACS Chem Biol 8:58–70

    Article  PubMed  CAS  Google Scholar 

  53. Fenton AW (2008) Allostery: an illustrated definition for the ‘second secret of life.’. Trends Biochem Sci 33:420–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Foda ZH, Seeliger MA (2014) An allosteric add-on. Nat Chem Biol 10:796–797

    Article  CAS  PubMed  Google Scholar 

  55. Foda ZH, Shan Y, Kim ET, Shaw DE, Seeliger MA (2015) A dynamically coupled allosteric network underlies binding cooperativity in Src kinase. Nat Commun 6:5939

    Article  CAS  PubMed  Google Scholar 

  56. Gafurov B, Chen Y-D, Chalovich JM (2004) Ca(2+) and ionic strength dependencies of S1-ADP binding to actin-tropomyosin-troponin: regulatory implications. Biophys J 87:1825–1835. https://doi.org/10.1529/biophysj.104.043364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ganesan A, Coote ML, Barakat K (2017) Molecular dynamics-driven drug discovery: leaping forward with confidence. Drug Discov Today 22:249–269

    Article  CAS  PubMed  Google Scholar 

  58. Gangoso E, Talaverón R, Jaraíz-Rodríguez M, Domínguez-Prieto M, Ezan P, Koulakoff A, Medina JM, Giaume C, Tabernero A (2017) A c-Src inhibitor peptide based on connexin43 exerts neuroprotective effects through the inhibition of glial hemichannel activity. Front Mol Neurosci 10:418

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Gao Z-G, Jacobson KA (2013) Allosteric modulation and functional selectivity of G protein-coupled receptors. Drug Discov Today Technol 10:e237–e243

    Article  PubMed  Google Scholar 

  60. Gao J, Wells JA (2012) Identification of specific tethered inhibitors for caspase-5. Chem Biol Drug Des 79:209–215

    Article  CAS  PubMed  Google Scholar 

  61. Gao Y, Shen L, Honzatko RB (2014) Central cavity of fructose-1,6-bisphosphatase and the evolution of AMP/fructose 2,6-bisphosphate synergism in eukaryotic organisms. J Biol Chem 289:8450–8461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gardino AK, Villali J, Kivenson A, Lei M, Liu CF, Steindel P, Eisenmesser EZ, Labeikovsky W, Wolf-Watz M, Clarkson MW (2009) Transient non-native hydrogen bonds promote activation of a signaling protein. Cell 139:1109–1118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gasper PM, Fuglestad B, Komives EA, Markwick PRL, McCammon JA (2012) Allosteric networks in thrombin distinguish procoagulant vs. anticoagulant activities. Proc Natl Acad Sci U S A 109:21216–21222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Gentry PR, Sexton PM, Christopoulos A (2015) Novel allosteric modulators of G protein-coupled receptors. J Biol Chem 290:19478–19488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Gibbons DL, Pricl S, Kantarjian H, Cortes J, Quintás-Cardama A (2012) The rise and fall of gatekeeper mutations? the BCR-ABL1 T315I paradigm. Cancer 118:293–299

    Article  CAS  PubMed  Google Scholar 

  66. Gill-Thind JK, Dhankher P, D’Oyley JM, Sheppard TD, Millar NS (2014) Structurally similar allosteric modulators of α7 nicotinic acetylcholine receptors exhibit five distinct pharmacological effects. J Biol Chem 290:3552–3562

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Goldenberg O, Erez E, Nimrod G, Ben-Tal N (2008) The ConSurf-DB: pre-calculated evolutionary conservation profiles of protein structures. Nucleic Acids Res 37:D323–D327

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Goodey NM, Benkovic SJ (2008) Allosteric regulation and catalysis emerge via a common route. Nat Chem Biol 4:474–482

    Article  CAS  PubMed  Google Scholar 

  69. Greener JG, Sternberg MJE (2018) Structure-based prediction of protein allostery. Curr Opin Struct Biol 50:1–8

    Article  CAS  PubMed  Google Scholar 

  70. Grimm SS, Isacoff EY (2016) Allosteric substrate switching in a voltage sensing lipid phosphatase. Nat Chem Biol 12:261–267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Grover AK (2013) Use of allosteric targets in the discovery of safer drugs. Med Princ Pract 22:418–426

    Article  PubMed  PubMed Central  Google Scholar 

  72. Guarnera E, Berezovsky IN (2016) Allosteric sites: remote control in regulation of protein activity. Curr Opin Struct Biol 37:1–8

    Article  CAS  PubMed  Google Scholar 

  73. Gunasekaran K, Ma B, Nussinov R (2004) Is allostery an intrinsic property of all dynamic proteins? Proteins Struct Funct Bioinforma 57:433–443

    Article  CAS  Google Scholar 

  74. Halabi N, Rivoire O, Leibler S, Ranganathan R (2009) Protein sectors: evolutionary units of three-dimensional structure. Cell 138:774–786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Handley LD, Fuglestad B, Stearns K, Tonelli M, Fenwick RB, Markwick PRL, Komives EA (2017) NMR reveals a dynamic allosteric pathway in thrombin. Sci Rep 7:39575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hardy JA, Wells JA (2004) Searching for new allosteric sites in enzymes. Curr Opin Struct Biol 14:706–715

    Article  CAS  PubMed  Google Scholar 

  77. Hertig S, Latorraca NR, Dror RO (2016) Revealing atomic-level mechanisms of protein allostery with molecular dynamics simulations. PLoS Comput Biol 12:e1004746

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Hines JK, Fromm HJ, Honzatko RB (2007) Structures of activated fructose-1, 6-bisphosphatase from Escherichia coli: coordinate regulation of bacterial metabolism and the conservation of the r-state. J Biol Chem 282:11696–11704

    Article  CAS  PubMed  Google Scholar 

  79. Hocker HJ, Cho K-J, Chen C-YK, Rambahal N, Sagineedu SR, Shaari K, Stanslas J, Hancock JF, Gorfe AA (2013) Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function. Proc Natl Acad Sci U S A 110:10201–10206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Hu Y, Li S, Liu F, Geng L, Shu X, Zhang J (2015) Discovery of novel nonpeptide allosteric inhibitors interrupting the interaction of CDK2/cyclin A3 by virtual screening and bioassays. Bioorg Med Chem Lett 25:4069–4073

    Article  CAS  PubMed  Google Scholar 

  81. Huang Z, Zhu L, Cao Y, Wu G, Liu X, Chen Y, Wang Q, Shi T, Zhao Y, Wang Y, Li W, Li Y, Chen H, Chen G, Zhang J (2011) ASD: a comprehensive database of allosteric proteins and modulators. Nucleic Acids Res 39:D663–D669

    Article  CAS  PubMed  Google Scholar 

  82. Huang M, Lu S, Shi T, Zhao Y, Chen Y, Li X, Liu X, Huang Z, Zhang J (2013a) Conformational transition pathway in the activation process of allosteric glucokinase. PLoS One 8:e55857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Huang W, Lu S, Huang Z, Liu X, Mou L, Luo Y, Zhao Y, Liu Y, Chen Z, Hou T (2013b) Allosite: a method for predicting allosteric sites. Bioinformatics 29:2357–2359

    Article  CAS  PubMed  Google Scholar 

  84. Huang Z, Mou L, Shen Q, Lu S, Li C, Liu X, Wang G, Li S, Geng L, Liu Y (2014) ASD v2. 0: updated content and novel features focusing on allosteric regulation. Nucleic Acids Res 42:D510–D516

    Article  CAS  PubMed  Google Scholar 

  85. Huang M, Song K, Liu X, Lu S, Shen Q, Wang R, Gao J, Hong Y, Li Q, Ni D, Xu J, Chen G, Zhang J (2018) AlloFinder: a strategy for allosteric modulator discovery and allosterome analyses. Nucleic Acids Res 46:W451–W458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Isaacs JS, Xu W, Neckers L (2003) Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell 3:213–217

    Article  CAS  PubMed  Google Scholar 

  87. Isherwood SN, Robbins TW, Dalley JW, Pekcec A (2018) Bidirectional variation in glutamate efflux in the medial prefrontal cortex induced by selective positive and negative allosteric mGluR5 modulators. J Neurochem 145:111–124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Jacobson KA (2015) New paradigms in GPCR drug discovery. Biochem Pharmacol 98:541–555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Jaffe EK (2005) Morpheeins–a new structural paradigm for allosteric regulation. Trends Biochem Sci 30:490–497

    Article  CAS  PubMed  Google Scholar 

  90. Jaffe EK, Lawrence SH (2012) The morpheein model of allostery: evaluating proteins as potential morpheeins. In: Allostery. Springer, pp 217–231. https://doi.org/10.1007/978-1-61779-334-9

    Google Scholar 

  91. Johnson LN, Lewis RJ (2001) Structural basis for control by phosphorylation. Chem Rev 101:2209–2242

    Article  CAS  PubMed  Google Scholar 

  92. Kar G, Keskin O, Gursoy A, Nussinov R (2010) Allostery and population shift in drug discovery. Curr Opin Pharmacol 10:715–722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kenakin T (2007) Collateral efficacy in drug discovery: taking advantage of the good (allosteric) nature of 7TM receptors. Trends Pharmacol Sci 28:407–415

    Article  CAS  PubMed  Google Scholar 

  94. Kenakin TP (2017) Chapter 5 – allosteric drug effects. In: Kenakin TPBT-P in DD and D, 2nd edn. Academic Press, Amsterdam, pp 101–129

    Google Scholar 

  95. Kim S, Broströmer E, Xing D, Jin J, Chong S, Ge H, Wang S, Gu C, Yang L, Gao YQ, Su X, Sun Y, Xie XS (2013) Probing Allostery Through DNA. Science (80- ) 339:816–819

    Article  CAS  Google Scholar 

  96. Kim JG, Kim TW, Kim J, Ihee H (2015) Protein structural dynamics revealed by time-resolved X-ray solution scattering. Acc Chem Res 48:2200–2208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kityk R, Vogel M, Schlecht R, Bukau B, Mayer MP (2015) Pathways of allosteric regulation in Hsp70 chaperones. Nat Commun 6:8308

    Article  CAS  PubMed  Google Scholar 

  98. Knight ZA, Lin H, Shokat KM (2010) Targeting the cancer kinome through polypharmacology. Nat Rev Cancer 10:130–137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Kobilka BK, Deupi X (2007) Conformational complexity of G-protein-coupled receptors. Trends Pharmacol Sci 28:397–406

    Article  CAS  PubMed  Google Scholar 

  100. Korczynska M, Clark MJ, Valant C, Xu J, Von Moo E, Albold S, Weiss DR, Torosyan H, Huang W, Kruse AC, Lyda BR, May LT, Baltos J-A, Sexton PM, Kobilka BK, Christopoulos A, Shoichet BK, Sunahara RK (2018) Structure-based discovery of selective positive allosteric modulators of antagonists for the M2 muscarinic acetylcholine receptor. Proc Natl Acad Sci U S A 115:E2419–E2428. https://doi.org/10.1073/pnas.1718037115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kornev AP, Taylor SS (2015) Dynamics-driven allostery in protein kinases. Trends Biochem Sci 40:628–647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Koshland DE Jr, Némethy G, Filmer D (1966) Comparison of experimental binding data and theoretical models in proteins containing subunits. Biochemistry 5:365–385

    Article  CAS  PubMed  Google Scholar 

  103. Kruger FA, Overington JP (2012) Global analysis of small molecule binding to related protein targets. PLoS Comput Biol 8:e1002333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Kruse AC, Ring AM, Manglik A, Hu J, Hu K, Eitel K, Hübner H, Pardon E, Valant C, Sexton PM (2013) Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature 504:101–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lazareno S, Doležal V, Popham A, Birdsall NJM (2004) Thiochrome enhances acetylcholine affinity at muscarinic M4 receptors: receptor subtype selectivity via cooperativity rather than affinity. Mol Pharmacol 65:257–266

    Article  CAS  PubMed  Google Scholar 

  106. Lee J, Natarajan M, Nashine VC, Socolich M, Vo T, Russ WP, Benkovic SJ, Ranganathan R (2008) Surface sites for engineering allosteric control in proteins. Science (80- ) 322:438–442

    Article  CAS  Google Scholar 

  107. Lee Y, Choi S, Hyeon C (2014) Mapping the intramolecular signal transduction of G-protein coupled receptors. Proteins Struct Funct Bioinforma 82:727–743

    Article  CAS  Google Scholar 

  108. Levy ED, Teichmann SA (2013) Structural, evolutionary, and assembly principles of protein oligomerization. Prog Mol Biol Transl Sci 117:25–51

    Article  CAS  PubMed  Google Scholar 

  109. Li X, Chen Y, Lu S, Huang Z, Liu X, Wang Q, Shi T, Zhang J (2013) Toward an understanding of the sequence and structural basis of allosteric proteins. J Mol Graph Model 40:30–39

    Article  PubMed  CAS  Google Scholar 

  110. Liu X, Ahn S, Kahsai AW, Meng K-C, Latorraca NR, Pani B, Venkatakrishnan AJ, Masoudi A, Weis WI, Dror RO, Chen X, Lefkowitz RJ, Kobilka BK (2017) Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure. Nature 548:480–484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Lockless SW, Ranganathan R (1999) Evolutionarily conserved pathways of energetic connectivity in protein families. Science (80- ) 286:295–299

    Article  CAS  Google Scholar 

  112. Louet M, Seifert C, Hensen U, Gräter F (2015) Dynamic allostery of the catabolite activator protein revealed by interatomic forces. PLoS Comput Biol 11:e1004358

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Lu S, Zhang J (2017) Designed covalent allosteric modulators: an emerging paradigm in drug discovery. Drug Discov Today 22:447–453. https://doi.org/10.1016/j.drudis.2016.11.013

    Article  CAS  PubMed  Google Scholar 

  114. Lu S, Zhang J (2018) Small molecule allosteric modulators of G-protein-coupled receptors: drug–target interactions. J Med Chem. https://doi.org/10.1021/acs.jmedchem.7b01844

    Article  PubMed  CAS  Google Scholar 

  115. Lu S, Huang W, Zhang J (2014a) Recent computational advances in the identification of allosteric sites in proteins. Drug Discov Today 19:1595–1600

    Article  CAS  PubMed  Google Scholar 

  116. Lu S, Li S, Zhang J (2014b) Harnessing allostery: a novel approach to drug discovery. Med Res Rev 34:1242–1285

    Article  CAS  PubMed  Google Scholar 

  117. Lu S, Jang H, Muratcioglu S, Gursoy A, Keskin O, Nussinov R, Zhang J (2016) Ras conformational ensembles, allostery, and signaling. Chem Rev 116:6607–6665

    Article  CAS  PubMed  Google Scholar 

  118. Lu S, Ji M, Ni D, Zhang J (2017) Discovery of hidden allosteric sites as novel targets for allosteric drug design. Drug Discov Today 23:359–365

    Article  PubMed  CAS  Google Scholar 

  119. Lü W, Du J, Goehring A, Gouaux E (2017) Cryo-EM structures of the triheteromeric NMDA receptor and its allosteric modulation. Science (80- ) 355:eaal3729

    Article  CAS  Google Scholar 

  120. Lutkenhaus J, Pichoff S, Du S (2012) Bacterial cytokinesis: from Z ring to divisome. Cytoskeleton 69:778–790

    Article  CAS  PubMed  Google Scholar 

  121. Macpherson JA, Anastasiou D (2017) Allosteric regulation of metabolism in cancer: endogenous mechanisms and considerations for drug design. Curr Opin Biotechnol 48:102–110

    Article  CAS  PubMed  Google Scholar 

  122. Modesti M (2011) Fluorescent labeling of proteins. In: Single molecule analysis. Springer, New York, pp 101–120

    Chapter  Google Scholar 

  123. Monod J, Wyman J, Changeux J-P (1978) On the nature of allosteric transitions: a plausible model. In: Selected papers in molecular biology by Jacques Monod. Elsevier, Amsterdam, pp 593–623

    Chapter  Google Scholar 

  124. Motlagh HN, Wrabl JO, Li J, Hilser VJ (2014) The ensemble nature of allostery. Nature 508:331–339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Muchmore DB (2000) Raloxifene: a selective estrogen receptor modulator (SERM) with multiple target system effects. Oncologist 5:388–392

    Article  CAS  PubMed  Google Scholar 

  126. Newcombe J, Chatzidaki A, Sheppard TD, Topf M, Millar NS (2018) Diversity of nicotinic acetylcholine receptor positive allosteric modulators revealed by mutagenesis and a revised structural model. Mol Pharmacol 93:128–140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Ni D, Lu S, Zhang J (2018) Methods applied for the allosteric site revelation. Encycl Anal Chem:1–13. https://doi.org/10.1002/9780470027318.a9614

  128. Niu W, Wang J, Qian J, Wang M, Wu P, Chen F, Yan S (2018) Allosteric control of human cystathionine β-synthase activity by a redox active disulfide bond. J Biol Chem 293:2523–2533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Nussinov R (2016) Introduction to protein ensembles and allostery. Chem Rev 116:6263–6266

    Article  PubMed  CAS  Google Scholar 

  130. Nussinov R, Tsai C-J (2012) The different ways through which specificity works in orthosteric and allosteric drugs. Curr Pharm Des 18:1311–1316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Nussinov R, Tsai C-J (2013) Allostery in disease and in drug discovery. Cell 153:293–305

    Article  CAS  PubMed  Google Scholar 

  132. Nussinov R, Tsai C-J (2014) Unraveling structural mechanisms of allosteric drug action. Trends Pharmacol Sci 35:256–264

    Article  CAS  PubMed  Google Scholar 

  133. Nussinov R, Tsai C-J (2015) The design of covalent allosteric drugs. Annu Rev Pharmacol Toxicol 55:249–267

    Article  CAS  PubMed  Google Scholar 

  134. Nussinov R, Tsai C-J, Csermely P (2011) Allo-network drugs: harnessing allostery in cellular networks. Trends Pharmacol Sci 32:686–693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Nussinov R, Tsai C-J, Xin F, Radivojac P (2012) Allosteric post-translational modification codes. Trends Biochem Sci 37:447–455

    Article  CAS  PubMed  Google Scholar 

  136. Nussinov R, Ma B, Tsai C-J, Csermely P (2013) Allosteric conformational barcodes direct signaling in the cell. Structure 21:1509–1521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Nussinov R, Tsai C-J, Liu J (2014) Principles of allosteric interactions in cell signaling. J Am Chem Soc 136:17692–17701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Omer A, Prasad CVSS (2012) Designing allosteric modulators for active conformational state of m-glutamate G-protein coupled receptors. Bioinformation 8:170–174

    Article  PubMed  PubMed Central  Google Scholar 

  139. Otero LH, Rojas-Altuve A, Llarrull LI, Carrasco-López C, Kumarasiri M, Lastochkin E, Fishovitz J, Dawley M, Hesek D, Lee M, Johnson JW, Fisher JF, Chang M, Mobashery S, Hermoso JA (2013) How allosteric control of Staphylococcus aureus penicillin binding protein 2a enables methicillin resistance and physiological function. Proc Natl Acad Sci U S A 110:16808–16813

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Pan Y, Tsai C-J, Ma B, Nussinov R (2010) Mechanisms of transcription factor selectivity. Trends Genet 26:75–83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Panjkovich A, Daura X (2012) Exploiting protein flexibility to predict the location of allosteric sites. BMC Bioinformatics 13:273

    Article  PubMed  PubMed Central  Google Scholar 

  142. Patricelli MP, Janes MR, Li L-S, Hansen R, Peters U, Kessler LV, Chen Y, Kucharski JM, Feng J, Ely T, Chen JH, Firdaus SJ, Babbar A, Ren P, Liu Y (2016) Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov 6:316–329

    Article  CAS  PubMed  Google Scholar 

  143. Pfaff SJ, Fletterick RJ (2010) Hormone and co-regulator binding to the glucocorticoid receptor are allosterically coupled. J Biol Chem 285:15256–15267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Pinney MM, Natarajan A, Yabukarski F, Sanchez DM, Liu F, Liang R, Doukov T, Schwans JP, Martinez TJ, Herschlag D (2018) Structural coupling throughout the active site hydrogen bond networks of ketosteroid isomerase and photoactive yellow protein. J Am Chem Soc 140:9827–9843

    Article  CAS  PubMed  Google Scholar 

  145. Plattner N, Doerr S, De Fabritiis G, Noé F (2017) Complete protein–protein association kinetics in atomic detail revealed by molecular dynamics simulations and Markov modelling. Nat Chem 9:1005–1011

    Article  CAS  PubMed  Google Scholar 

  146. Popovych N, Sun S, Ebright RH, Kalodimos CG (2006) Dynamically driven protein allostery. Nat Struct Mol Biol 13:831–838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Prakash P, Sayyed-Ahmad A, Gorfe AA (2015) pMD-Membrane: a method for ligand binding site Identification in membrane-bound proteins. PLoS Comput Biol 11:e1004469

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Rabiller M, Getlik M, Klüter S, Richters A, Tückmantel S, Simard JR, Rauh D (2010) Proteus in the world of proteins: conformational changes in protein kinases. Arch der Pharm An Int J Pharm Med Chem 343:193–206

    Article  CAS  Google Scholar 

  149. Ramírez-Aportela E, López-Blanco JR, Andreu JM, Chacón P (2014) Understanding nucleotide-regulated FtsZ filament dynamics and the monomer assembly switch with large-scale atomistic simulations. Biophys J 107:2164–2176

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Rask-Andersen M, Zhang J, Fabbro D, Schiöth HB (2014) Advances in kinase targeting: current clinical use and clinical trials. Trends Pharmacol Sci 35:604–620

    Article  CAS  PubMed  Google Scholar 

  151. Rescifina A, Scala A, Sciortino MT, Colao I, Siracusano G, Mazzaglia A, Chiacchio U, Grassi G (2015) Decorated 6, 6′, 7, 7′-tetrahydro-1 H, 1′ H-2, 3′-biindole scaffold as promising candidate for recognition of the CDK2 allosteric site. Medchemcomm 6:311–318

    Article  CAS  Google Scholar 

  152. Reynolds KA, McLaughlin RN, Ranganathan R (2011) Hot spots for allosteric regulation on protein surfaces. Cell 147:1564–1575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Rose PW, Bi C, Bluhm WF, Christie CH, Dimitropoulos D, Dutta S, Green RK, Goodsell DS, Prlić A, Quesada M (2012) The RCSB Protein Data Bank: new resources for research and education. Nucleic Acids Res 41:D475–D482

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Rose PW, Prlić A, Altunkaya A, Bi C, Bradley AR, Christie CH, Di Costanzo L, Duarte JM, Dutta S, Feng Z, Green RK, Goodsell DS, Hudson B, Kalro T, Lowe R, Ezra Peisach SKB (2017) The RCSB protein data bank: integrative view of protein, gene and 3D structural information. Nucleic Acids Res 45:D271–D281

    Article  CAS  PubMed  Google Scholar 

  155. Roskoski R (2004) Src protein–tyrosine kinase structure and regulation. Biochem Biophys Res Commun 324:1155–1164

    Article  CAS  PubMed  Google Scholar 

  156. Roth BL, Irwin JJ, Shoichet BK (2017) Discovery of new GPCR ligands to illuminate new biology. Nat Chem Biol 13:1143–1151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Ruff EF, Muretta JM, Thompson AR, Lake EW, Cyphers S, Albanese SK, Hanson SM, Behr JM, Thomas DD, Chodera JD (2018) A dynamic mechanism for allosteric activation of Aurora kinase A by activation loop phosphorylation. Elife 7:e32766

    Article  PubMed  PubMed Central  Google Scholar 

  158. Saavedra HG, Wrabl JO, Anderson JA, Li J, Hilser VJ (2018) Dynamic allostery can drive cold adaptation in enzymes. Nature 558:324–328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Sadowsky JD, Burlingame MA, Wolan DW, McClendon CL, Jacobson MP, Wells JA (2011) Turning a protein kinase on or off from a single allosteric site via disulfide trapping. Proc Natl Acad Sci U S A 108:6056–6061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Scheer JM, Romanowski MJ, Wells JA (2006) A common allosteric site and mechanism in caspases. Proc Natl Acad Sci U S A 103:7595–7600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Schelshorn D, Joly F, Mutel S, Hampe C, Breton B, Mutel V, Lütjens R (2012) Lateral allosterism in the glucagon receptor family: glucagon-like peptide 1 induces G-protein-coupled receptor heteromer formation. Mol Pharmacol 81:309–318

    Article  CAS  PubMed  Google Scholar 

  162. Schiffmann A, Gimpl G (2018) Sodium functions as a negative allosteric modulator of the oxytocin receptor. Biochim Biophys Acta – Biomembr 1860:1301–1308

    Article  CAS  PubMed  Google Scholar 

  163. Schnell JR, Dyson HJ, Wright PE (2004) Structure, dynamics, and catalytic function of dihydrofolate reductase. Annu Rev Biophys Biomol Struct 33:119–140

    Article  CAS  PubMed  Google Scholar 

  164. Sebastian B, Kakizuka A, Hunter T (1993) Cdc25M2 activation of cyclin-dependent kinases by dephosphorylation of threonine-14 and tyrosine-15. Proc Natl Acad Sci U S A 90:3521–3524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Shen Q, Wang G, Li S, Liu X, Lu S, Chen Z, Song K, Yan J, Geng L, Huang Z, Huang W, Chen G, Zhang J (2016) ASD v3.0: unraveling allosteric regulation with structural mechanisms and biological networks. Nucleic Acids Res 44:D527–D535

    Article  CAS  PubMed  Google Scholar 

  166. Shi Y (2014) A glimpse of structural biology through X-ray crystallography. Cell 159:995–1014

    Article  CAS  PubMed  Google Scholar 

  167. Shukla D, Meng Y, Roux B, Pande VS (2014) Activation pathway of Src kinase reveals intermediate states as targets for drug design. Nat Commun 5:3397

    Article  PubMed  CAS  Google Scholar 

  168. Sinha N, Nussinov R (2001) Point mutations and sequence variability in proteins: redistributions of preexisting populations. Proc Natl Acad Sci U S A 98:3139–3144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Skora L, Mestan J, Fabbro D, Jahnke W, Grzesiek S (2013) NMR reveals the allosteric opening and closing of Abelson tyrosine kinase by ATP-site and myristoyl pocket inhibitors. Proc Natl Acad Sci U S A 110:E4437–E4445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Smith RD, Lu J, Carlson HA (2017) Are there physicochemical differences between allosteric and competitive ligands? PLoS Comput Biol 13:e1005813

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Song GJ, Jung M, Kim J-H, Park H, Rahman MH, Zhang S, Zhang Z-Y, Park DH, Kook H, Lee I-K (2016) A novel role for protein tyrosine phosphatase 1B as a positive regulator of neuroinflammation. J Neuroinflammation 13:86

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Song K, Liu X, Huang W, Lu S, Shen Q, Zhang L, Zhang J (2017) Improved method for the identification and validation of allosteric sites. J Chem Inf Model 57:2358–2363

    Article  CAS  PubMed  Google Scholar 

  173. Stetz G, Verkhivker GM (2017) Computational analysis of residue interaction networks and coevolutionary relationships in the Hsp70 chaperones: a community-hopping model of allosteric regulation and communication. PLoS Comput Biol 13:e1005299

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Stothard P (2000) The sequence manipulation suite: JavaScript programs for analyzing and formatting protein and DNA sequences. Biotechniques 28:1102–1104

    Article  CAS  PubMed  Google Scholar 

  175. Strickland D, Moffat K, Sosnick TR (2008) Light-activated DNA binding in a designed allosteric protein. Proc Natl Acad Sci U S A 105:10709–10714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Szilágyi A, Nussinov R, Csermely P (2013) Allo-network drugs: extension of the allosteric drug concept to protein-protein interaction and signaling networks. Curr Top Med Chem 13:64–77

    Article  PubMed  Google Scholar 

  177. Tan CM, Therien AG, Lu J, Lee SH, Caron A, Gill CJ, Lebeau-Jacob C, Benton-Perdomo L, Monteiro JM, Pereira PM (2012) Restoring methicillin-resistant Staphylococcus aureus susceptibility to β-lactam antibiotics. Sci Transl Med 4:126ra35

    PubMed  Google Scholar 

  178. Taylor SS, Kornev AP (2011) Protein kinases: evolution of dynamic regulatory proteins. Trends Biochem Sci 36:65–77

    Article  CAS  PubMed  Google Scholar 

  179. Teşileanu T, Colwell LJ, Leibler S (2015) Protein sectors: Statistical coupling analysis versus conservation. PLoS Comput Biol 11:e1004091

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  180. Thal DM, Glukhova A, Sexton PM, Christopoulos A (2018) Structural insights into G-protein-coupled receptor allostery. Nature 559:45–53

    Article  CAS  PubMed  Google Scholar 

  181. Tompa P (2012) Intrinsically disordered proteins: a 10-year recap. Trends Biochem Sci 37:509–516

    Article  CAS  PubMed  Google Scholar 

  182. Tsai C-J, Nussinov R (2014) A Unified View of “How Allostery Works.”. PLOS Comput Biol 10:e1003394

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  183. Tzeng S-R, Kalodimos CG (2011) Protein dynamics and allostery: an NMR view. Curr Opin Struct Biol 21:62–67. https://doi.org/10.1016/j.sbi.2010.10.007

    Article  CAS  PubMed  Google Scholar 

  184. Urwyler S (2011) Allosteric modulation of family C G-protein-coupled receptors: from molecular insights to therapeutic perspectives. Pharmacol Rev 63:59–126

    Article  CAS  PubMed  Google Scholar 

  185. Van Wart AT, Durrant J, Votapka L, Amaro RE (2014) Weighted implementation of suboptimal paths (WISP): an optimized algorithm and tool for dynamical network analysis. J Chem Theory Comput 10:511–517

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. van Westen GJP, Gaulton A, Overington JP (2014) Chemical, target, and bioactive properties of allosteric modulation. PLOS Comput Biol 10:e1003559

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Verespy S III, Mehta AY, Afosah D, Al-Horani RA, Desai UR (2016) Allosteric partial inhibition of monomeric proteases. Sulfated coumarins induce regulation, not just inhibition, of thrombin. Sci Rep 6:24043

    Article  CAS  PubMed  Google Scholar 

  188. Verkhivker GM (2016) Molecular dynamics simulations and modelling of the residue interaction networks in the BRAF kinase complexes with small molecule inhibitors: probing the allosteric effects of ligand-induced kinase dimerization and paradoxical activation. Mol Biosyst 12:3146–3165

    Article  CAS  PubMed  Google Scholar 

  189. Verkhivker GM (2017) Leveraging structural diversity and allosteric regulatory mechanisms of protein kinases in the discovery of small molecule inhibitors. Curr Med Chem 24:4838–4872

    CAS  PubMed  Google Scholar 

  190. Viganò E, Diamond CE, Spreafico R, Balachander A, Sobota RM, Mortellaro A (2015) Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes. Nat Commun 6:8761

    Article  PubMed  CAS  Google Scholar 

  191. Wagner JR, Lee CT, Durrant JD, Malmstrom RD, Feher VA, Amaro RE (2016) Emerging computational methods for the rational discovery of allosteric drugs. Chem Rev 116:6370–6390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Wei H, Mo J, Tao L, Russell RJ, Tymiak AA, Chen G, Iacob RE, Engen JR (2014) Hydrogen/deuterium exchange mass spectrometry for probing higher order structure of protein therapeutics: methodology and applications. Drug Discov Today 19:95–102

    Article  CAS  PubMed  Google Scholar 

  193. Wenthur CJ, Gentry PR, Mathews TP, Lindsley CW (2014) Drugs for allosteric sites on receptors. Annu Rev Pharmacol Toxicol 54:165–184

    Article  CAS  PubMed  Google Scholar 

  194. Whittaker SR, Barlow C, Martin MP, Mancusi C, Wagner S, Self A, Barrie E, Te Poele R, Sharp S, Brown N (2018) Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor. Mol Oncol 12:287–304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Wilhelm A, Lopez-Garcia LA, Busschots K, Fröhner W, Maurer F, Boettcher S, Zhang H, Schulze JO, Biondi RM, Engel M (2012) 2-(3-Oxo-1,3-diphenylpropyl)malonic acids as potent allosteric ligands of the PIF pocket of phosphoinositide-dependent Kinase-1: development and prodrug concept. J Med Chem 55:9817–9830. https://doi.org/10.1021/jm3010477

    Article  CAS  PubMed  Google Scholar 

  196. Wootten D, Christopoulos A, Sexton PM (2013) Emerging paradigms in GPCR allostery: implications for drug discovery. Nat Rev Drug Discov 12:630–644

    Article  CAS  PubMed  Google Scholar 

  197. Wright PE, Dyson HJ (2014) Intrinsically disordered proteins in cellular signalling and regulation. Nat Rev Mol Cell Biol 16:18–29

    Article  CAS  Google Scholar 

  198. Wu P, Clausen MH, Nielsen TE (2015) Allosteric small-molecule kinase inhibitors. Pharmacol Ther 156:59–68

    Article  CAS  PubMed  Google Scholar 

  199. Xu Y, Smith R, Vivoli M, Ema M, Goos N, Gehrke S, Harmer NJ, Wagner GK (2017) Covalent inhibitors of LgtC: a blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases. Bioorg Med Chem 25:3182–3194

    Article  CAS  PubMed  Google Scholar 

  200. Xu Y, Wang S, Hu Q, Gao S, Ma X, Zhang W, Shen Y, Chen F, Lai L, Pei J (2018) CavityPlus: a web server for protein cavity detection with pharmacophore modelling, allosteric site identification and covalent ligand binding ability prediction. Nucleic Acids Res 46:W374–W379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Yang J-S, Seo SW, Jang S, Jung GY, Kim S (2012) Rational engineering of enzyme allosteric regulation through sequence evolution analysis. PLoS Comput Biol 8:e1002612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Yau M-K, Liu L, Fairlie DP (2013) Toward drugs for protease-activated receptor 2 (PAR2). J Med Chem 56:7477–7497

    Article  CAS  PubMed  Google Scholar 

  203. Youssef EA, Berry-Kravis E, Czech C, Hagerman RJ, Hessl D, Wong CY, Rabbia M, Deptula D, John A, Kinch R (2018) Effect of the mGluR5-NAM basimglurant on behavior in adolescents and adults with Fragile X syndrome in a randomized, double-blind, placebo-controlled trial: fragXis phase 2 results. Neuropsychopharmacology 43:503–512

    Article  CAS  PubMed  Google Scholar 

  204. Zhu R, Song Y, Liu H, Yang Y, Wang S, Yi C, Chen PR (2017) Allosteric histidine switch for regulation of intracellular zinc(II) fluctuation. Proc Natl Acad Sci U S A 114:13661–13666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Zuehlke AD, Moses MA, Neckers L (2018) Heat shock protein 90: its inhibition and function. Phil Trans R Soc B 373:20160527

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (21778037; Shanghai Health and Family Planning Commission (20154Y0058), the Fundamental Research Funds for the Central Universities, and the Chun-Tsung project (No.2018-02-04).

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  1. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

    Xinheng He, Duan Ni, Shaoyong Lu & Jian Zhang

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  1. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

    Jian Zhang

  2. Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA, Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Ruth Nussinov

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He, X., Ni, D., Lu, S., Zhang, J. (2019). Characteristics of Allosteric Proteins, Sites, and Modulators. In: Zhang, J., Nussinov, R. (eds) Protein Allostery in Drug Discovery. Advances in Experimental Medicine and Biology, vol 1163. Springer, Singapore. https://doi.org/10.1007/978-981-13-8719-7_6

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