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Interrogating Regulatory Mechanisms in Signaling Proteins by Allosteric Inhibitors and Activators: A Dynamic View Through the Lens of Residue Interaction Networks

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Protein Allostery in Drug Discovery

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

Abstract

Computational studies of allosteric interactions have witnessed a recent renaissance fueled by the growing interest in modeling of the complex molecular assemblies and biological networks. Allosteric interactions in protein structures allow for molecular communication in signal transduction networks. In this chapter, we discuss recent developments in understanding of allosteric mechanisms and interactions of protein systems, particularly in the context of structural, functional, and computational studies of allosteric inhibitors and activators. Computational and experimental approaches and advances in understanding allosteric regulatory mechanisms are reviewed to provide a systematic and critical view of the current progress in the development of allosteric modulators and highlight most challenging questions in the field. The abundance and diversity of genetic, structural, and biochemical data underlies the complexity of mechanisms by which targeted and personalized drugs can combat mutational profiles in protein kinases. Structural and computational studies of protein kinases have generated in recent decade significant insights that allowed leveraging knowledge about conformational diversity and allosteric regulation of protein kinases in the design and discovery of novel kinase drugs. We discuss recent developments in understanding multilayered allosteric regulatory machinery of protein kinases and provide a systematic view of the current state in understanding molecular basis of allostery mediated by kinase inhibitors and activators. In conclusion, we highlight the current status and future prospects of computational biology approaches in bridging the basic science of protein kinases with the discovery of anticancer therapies.

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References

  1. Adrian FJ, Ding Q, Sim T, Velentza A, Sloan C, Liu Y, Zhang G, Hur W, Ding S, Manley P, Mestan J, Fabbro D, Gray NS (2006) Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Nat Chem Biol 2(2):95–102

    Article  CAS  PubMed  Google Scholar 

  2. Aguilar D, Oliva B, Marino Buslje C (2012) Mapping the mutual information network of enzymatic families in the protein structure to unveil functional features. PLoS One 7(7):e41430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Amodeo GA, Rudolph MJ, Tong L (2007) Crystal structure of the heterotrimer core of Saccharomyces cerevisiae AMPK homologue SNF1. Nature 449(7161):492–495

    Article  CAS  PubMed  Google Scholar 

  4. Artim SC, Mendrola JM, Lemmon MA (2012) Assessing the range of kinase autoinhibition mechanisms in the insulin receptor family. Biochem J 448(2):213–220

    Article  CAS  PubMed  Google Scholar 

  5. Ashwell MA, Lapierre JM, Brassard C, Bresciano K, Bull C, Cornell-Kennon S, Eathiraj S, France DS, Hall T, Hill J, Kelleher E, Khanapurkar S, Kizer D, Koerner S, Link J, Liu Y, Makhija S, Moussa M, Namdev N, Nguyen K, Nicewonger R, Palma R, Szwaya J, Tandon M, Uppalapati U, Vensel D, Volak LP, Volckova E, Westlund N, Wu H, Yang RY, Chan TC (2012) Discovery and optimization of a series of 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amines: orally bioavailable, selective, and potent ATP-independent Akt inhibitors. J Med Chem 55(11):5291–5310

    Article  CAS  PubMed  Google Scholar 

  6. Bahar I, Chennubhotla C, Tobi D (2007) Intrinsic dynamics of enzymes in the unbound state and relation to allosteric regulation. Curr Opin Struct Biol 17(6):633–640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bahar I, Lezon TR, Yang LW, Eyal E (2010) Global dynamics of proteins: bridging between structure and function. Annu Rev Biophys 39:23–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bahar I, Rader AJ (2005) Coarse-grained normal mode analysis in structural biology. Curr Opin Struct Biol 15(5):586–592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Barila D, Superti-Furga G (1998) An intramolecular SH3-domain interaction regulates c-Abl activity. Nat Genet 18(3):280–282

    Article  CAS  PubMed  Google Scholar 

  10. Barnett SF, Defeo-Jones D, Fu S, Hancock PJ, Haskell KM, Jones RE, Kahana JA, Kral AM, Leander K, Lee LL, Malinowski J, McAvoy EM, Nahas DD, Robinson RG, Huber HE (2005) Identification and characterization of pleckstrin-homology-domain-dependent and isoenzyme-specific Akt inhibitors. Biochem J 385(Pt 2):399–408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Berlow RB, Dyson HJ, Wright PE (2018) Expanding the paradigm: intrinsically disordered proteins and allosteric regulation. J Mol Biol 430(16):2309–2320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Betzi S, Alam R, Martin M, Lubbers DJ, Han H, Jakkaraj SR, Georg GI, Schonbrunn E (2011) Discovery of a potential allosteric ligand binding site in CDK2. ACS Chem Biol 6(5):492–501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bhattacharya S, Vaidehi N (2014) Differences in allosteric communication pipelines in the inactive and active states of a GPCR. Biophys J 107(2):422–434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bhattacharya SK, Aspnes GE, Bagley SW, Boehm M, Brosius AD, Buckbinder L, Chang JS, Dibrino J, Eng H, Frederick KS, Griffith DA, Griffor MC, Guimaraes CR, Guzman-Perez A, Han S, Kalgutkar AS, Klug-McLeod J, Garcia-Irizarry C, Li J, Lippa B, Price DA, Southers JA, Walker DP, Wei L, Xiao J, Zawistoski MP, Zhao X (2012) Identification of novel series of pyrazole and indole-urea based DFG-out PYK2 inhibitors. Bioorg Med Chem Lett 22(24):7523–7529

    Article  CAS  PubMed  Google Scholar 

  15. Bhattacharyya M, Vishveshwara S (2010) Elucidation of the conformational free energy landscape in H.pylori LuxS and its implications to catalysis. BMC Struct Biol 10:27

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Bhattacharyya M, Vishveshwara S (2011) Probing the allosteric mechanism in pyrrolysyl-tRNA synthetase using energy-weighted network formalism. Biochemistry 50(28):6225–6236

    Article  CAS  PubMed  Google Scholar 

  17. Bishop AC, Chen VL (2009) Brought to life: targeted activation of enzyme function with small molecules. J Chem Biol 2(1):1–9

    Article  PubMed  Google Scholar 

  18. Blacklock K, Verkhivker GM (2014) Computational modeling of allosteric regulation in the Hsp90 chaperones: a statistical ensemble analysis of protein structure networks and allosteric communications. PLoS Comput Biol 10(6):21

    Article  CAS  Google Scholar 

  19. Bock A, Bermudez M, Krebs F, Matera C, Chirinda B, Sydow D, Dallanoce C, Holzgrabe U, De Amici M, Lohse MJ, Wolber G, Mohr K (2016) Ligand binding ensembles determine graded agonist efficacies at a G protein-coupled receptor. J Biol Chem 291(31):16375–16389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Boggon TJ, Eck MJ (2004) Structure and regulation of Src family kinases. Oncogene 23(48):7918–7927

    Article  CAS  PubMed  Google Scholar 

  21. Bose R, Zhang X (2009) The ErbB kinase domain: structural perspectives into kinase activation and inhibition. Exp Cell Res 315(4):649–658

    Article  CAS  PubMed  Google Scholar 

  22. Bowman GR, Geissler PL (2012) Equilibrium fluctuations of a single folded protein reveal a multitude of potential cryptic allosteric sites. Proc Natl Acad Sci U S A 109(29):11681–11686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Brasher BB, Roumiantsev S, Van Etten RA (2001) Mutational analysis of the regulatory function of the c-Abl Src homology 3 domain. Oncogene 20(53):7744–7752

    Article  CAS  PubMed  Google Scholar 

  24. Brinda KV, Vishveshwara S (2005) A network representation of protein structures: implications for protein stability. Biophys J 89(6):4159–4170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Brinda KV, Vishveshwara S (2010) Random network behaviour of protein structures. Mol BioSyst 6(2):391–398

    Article  CAS  PubMed  Google Scholar 

  26. Buchenberg S, Sittel F, Stock G (2017) Time-resolved observation of protein allosteric communication. Proc Natl Acad Sci U S A 114(33):E6804–e6811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Budas GR, Koyanagi T, Churchill EN, Mochly-Rosen D (2007) Competitive inhibitors and allosteric activators of protein kinase C isoenzymes: a personal account and progress report on transferring academic discoveries to the clinic. Biochem Soc Trans 35(Pt 5):1021–1026

    Article  CAS  PubMed  Google Scholar 

  28. Busschots K, Lopez-Garcia LA, Lammi C, Stroba A, Zeuzem S, Piiper A, Alzari PM, Neimanis S, Arencibia JM, Engel M, Schulze JO, Biondi RM (2012) Substrate-selective inhibition of protein kinase PDK1 by small compounds that bind to the PIF-pocket allosteric docking site. Chem Biol 19(9):1152–1163

    Article  CAS  PubMed  Google Scholar 

  29. Chakrabarti S, Panchenko AR (2009) Coevolution in defining the functional specificity. Proteins 75(1):231–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chakrabarti S, Panchenko AR (2010) Structural and functional roles of coevolved sites in proteins. PLoS One 5(1):e8591

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  32. Changeux JP, Edelstein SJ (2005) Allosteric mechanisms of signal transduction. Science 308(5727):1424–1428

    Article  CAS  PubMed  Google Scholar 

  33. Chen S, Dumitrescu TP, Smithgall TE, Engen JR (2008a) Abl N-terminal cap stabilization of SH3 domain dynamics. Biochemistry 47(21):5795–5803

    Article  CAS  PubMed  Google Scholar 

  34. Chen S, O’Reilly LP, Smithgall TE, Engen JR (2008b) Tyrosine phosphorylation in the SH3 domain disrupts negative regulatory interactions within the c-Abl kinase core. J Mol Biol 383(2):414–423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chennubhotla C, Bahar I (2006) Markov propagation of allosteric effects in biomolecular systems: application to GroEL-GroES. Mol Syst Biol 2:36

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Chennubhotla C, Bahar I (2007) Signal propagation in proteins and relation to equilibrium fluctuations. PLoS Comput Biol 3(9):1716–1726

    Article  CAS  PubMed  Google Scholar 

  37. Chennubhotla C, Yang Z, Bahar I (2008) Coupling between global dynamics and signal transduction pathways: a mechanism of allostery for chaperonin GroEL. Mol BioSyst 4(4):287–292

    Article  CAS  PubMed  Google Scholar 

  38. Choi JH, Laurent AH, Hilser VJ, Ostermeier M (2015) Design of protein switches based on an ensemble model of allostery. Nat Commun 6:6968

    Article  CAS  PubMed  Google Scholar 

  39. Christodoulou MS, Caporuscio F, Restelli V, Carlino L, Cannazza G, Costanzi E, Citti C, Lo Presti L, Pisani P, Battistutta R, Broggini M, Passarella D, Rastelli G (2017) Probing an allosteric pocket of CDK2 with small molecules. ChemMedChem 12(1):33–41

    Article  CAS  PubMed  Google Scholar 

  40. Comess KM, Sun C, Abad-Zapatero C, Goedken ER, Gum RJ, Borhani DW, Argiriadi M, Groebe DR, Jia Y, Clampit JE, Haasch DL, Smith HT, Wang S, Song D, Coen ML, Cloutier TE, Tang H, Cheng X, Quinn C, Liu B, Xin Z, Liu G, Fry EH, Stoll V, Ng TI, Banach D, Marcotte D, Burns DJ, Calderwood DJ, Hajduk PJ (2011) Discovery and characterization of non-ATP site inhibitors of the mitogen activated protein (MAP) kinases. ACS Chem Biol 6(3):234–244

    Article  CAS  PubMed  Google Scholar 

  41. Cool B, Zinker B, Chiou W, Kifle L, Cao N, Perham M, Dickinson R, Adler A, Gagne G, Iyengar R, Zhao G, Marsh K, Kym P, Jung P, Camp HS, Frevert E (2006) Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab 3(6):403–416

    Article  CAS  PubMed  Google Scholar 

  42. Cooper A, Dryden DT (1984) Allostery without conformational change. A plausible model. Eur Biophys J 11(2):103–109

    Article  CAS  PubMed  Google Scholar 

  43. Cowan-Jacob SW, Jahnke W, Knapp S (2014) Novel approaches for targeting kinases: allosteric inhibition, allosteric activation and pseudokinases. Future Med Chem 6(5):541–561

    Article  CAS  PubMed  Google Scholar 

  44. Cox KJ, Shomin CD, Ghosh I (2011) Tinkering outside the kinase ATP box: allosteric (type IV) and bivalent (type V) inhibitors of protein kinases. Future Med Chem 3(1):29–43

    Article  CAS  PubMed  Google Scholar 

  45. Csermely P, Korcsmaros T, Kiss HJ, London G, Nussinov R (2013) Structure and dynamics of molecular networks: a novel paradigm of drug discovery: a comprehensive review. Pharmacol Ther 138(3):333–408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Csermely P, Palotai R, Nussinov R (2010) Induced fit, conformational selection and independent dynamic segments: an extended view of binding events. Trends Biochem Sci 35(10):539–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Csermely P, Sandhu KS, Hazai E, Hoksza Z, Kiss HJ, Miozzo F, Veres DV, Piazza F, Nussinov R (2012) Disordered proteins and network disorder in network descriptions of protein structure, dynamics and function: hypotheses and a comprehensive review. Curr Protein Pept Sci 13(1):19–33

    Article  CAS  PubMed  Google Scholar 

  48. Dam TK, Roy R, Page D, Brewer CF (2002) Negative cooperativity associated with binding of multivalent carbohydrates to lectins. Thermodynamic analysis of the "multivalency effect". Biochemistry 41(4):1351–1358

    Article  CAS  PubMed  Google Scholar 

  49. Dar AC, Shokat KM (2011) The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling. Annu Rev Biochem 80:769–795

    Article  CAS  PubMed  Google Scholar 

  50. de Juan D, Pazos F, Valencia A (2013) Emerging methods in protein co-evolution. Nat Rev Genet 14(4):249–261

    Article  PubMed  CAS  Google Scholar 

  51. del Sol A, Tsai CJ, Ma B, Nussinov R (2009) The origin of allosteric functional modulation: multiple pre-existing pathways. Structure 17(8):1042–1050

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Di Paola L, Giuliani A (2015) Protein contact network topology: a natural language for allostery. Curr Opin Struct Biol 31:43–48

    Article  PubMed  CAS  Google Scholar 

  53. Dokholyan NV (2016) Controlling allosteric networks in proteins. Chem Rev 116(11):6463–6487

    Article  CAS  PubMed  Google Scholar 

  54. Dong Q, Dougan DR, Gong X, Halkowycz P, Jin B, Kanouni T, O’Connell SM, Scorah N, Shi L, Wallace MB, Zhou F (2011) Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer. Bioorg Med Chem Lett 21(5):1315–1319

    Article  CAS  PubMed  Google Scholar 

  55. Endicott JA, Noble ME, Johnson LN (2012) The structural basis for control of eukaryotic protein kinases. Annu Rev Biochem 81:587–613

    Article  CAS  PubMed  Google Scholar 

  56. Engel M, Hindie V, Lopez-Garcia LA, Stroba A, Schaeffer F, Adrian I, Imig J, Idrissova L, Nastainczyk W, Zeuzem S, Alzari PM, Hartmann RW, Piiper A, Biondi RM (2006) Allosteric activation of the protein kinase PDK1 with low molecular weight compounds. EMBO J 25(23):5469–5480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Engen JR, Wales TE, Hochrein JM, Meyn MA 3rd, Banu Ozkan S, Bahar I, Smithgall TE (2008) Structure and dynamic regulation of Src-family kinases. Cell Mol Life Sci 65(19):3058–3073

    Article  CAS  PubMed  Google Scholar 

  58. Fabbro D (2015) 25 years of small molecular weight kinase inhibitors: potentials and limitations. Mol Pharmacol 87(5):766–775

    Article  CAS  PubMed  Google Scholar 

  59. Fang Z, Grutter C, Rauh D (2013) Strategies for the selective regulation of kinases with allosteric modulators: exploiting exclusive structural features. ACS Chem Biol 8(1):58–70

    Article  CAS  PubMed  Google Scholar 

  60. Fang Z, Simard JR, Plenker D, Nguyen HD, Phan T, Wolle P, Baumeister S, Rauh D (2015) Discovery of inter-domain stabilizers-a novel assay system for allosteric akt inhibitors. ACS Chem Biol 10(1):279–288

    Article  CAS  PubMed  Google Scholar 

  61. Fasano M, Della Corte CM, Califano R, Capuano A, Troiani T, Martinelli E, Ciardiello F, Morgillo F (2014) Type III or allosteric kinase inhibitors for the treatment of non-small cell lung cancer. Expert Opin Investig Drugs 23(6):809–821

    Article  CAS  PubMed  Google Scholar 

  62. Feher VA, Durrant JD, Van Wart AT, Amaro RE (2014) Computational approaches to mapping allosteric pathways. Curr Opin Struct Biol 25:98–103

    Article  CAS  PubMed  Google Scholar 

  63. Ferguson KM (2008) Structure-based view of epidermal growth factor receptor regulation. Annu Rev Biophys 37:353–373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ferreon AC, Ferreon JC, Wright PE, Deniz AA (2013) Modulation of allostery by protein intrinsic disorder. Nature 498(7454):390–394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Fischmann TO, Smith CK, Mayhood TW, Myers JE, Reichert P, Mannarino A, Carr D, Zhu H, Wong J, Yang RS, Le HV, Madison VS (2009) Crystal structures of MEK1 binary and ternary complexes with nucleotides and inhibitors. Biochemistry 48(12):2661–2674

    Article  CAS  PubMed  Google Scholar 

  66. 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 

  67. Frederick KK, Marlow MS, Valentine KG, Wand AJ (2007) Conformational entropy in molecular recognition by proteins. Nature 448(7151):325–329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Garcia-Pino A, Balasubramanian S, Wyns L, Gazit E, De Greve H, Magnuson RD, Charlier D, van Nuland NA, Loris R (2010) Allostery and intrinsic disorder mediate transcription regulation by conditional cooperativity. Cell 142(1):101–111

    Article  CAS  PubMed  Google Scholar 

  69. Ghosh A, Sakaguchi R, Liu C, Vishveshwara S, Hou YM (2011) Allosteric communication in cysteinyl tRNA synthetase: a network of direct and indirect readout. J Biol Chem 286(43):37721–37731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ghosh A, Vishveshwara S (2007) A study of communication pathways in methionyl- tRNA synthetase by molecular dynamics simulations and structure network analysis. Proc Natl Acad Sci U S A 104(40):15711–15716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ghosh A, Vishveshwara S (2008) Variations in clique and community patterns in protein structures during allosteric communication: investigation of dynamically equilibrated structures of methionyl tRNA synthetase complexes. Biochemistry 47(44):11398–11407

    Article  CAS  PubMed  Google Scholar 

  72. Gloor GB, Martin LC, Wahl LM, Dunn SD (2005) Mutual information in protein multiple sequence alignments reveals two classes of coevolving positions. Biochemistry 44(19):7156–7165

    Article  CAS  PubMed  Google Scholar 

  73. Goncearenco A, Mitternacht S, Yong T, Eisenhaber B, Eisenhaber F, Berezovsky IN (2013) SPACER: server for predicting allosteric communication and effects of regulation. Nucleic Acids Res 41(Web Server issue):W266–W272

    Article  PubMed  PubMed Central  Google Scholar 

  74. Good MC, Zalatan JG, Lim WA (2011) Scaffold proteins: hubs for controlling the flow of cellular information. Science 332(6030):680–686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Grebien F, Hantschel O, Wojcik J, Kaupe I, Kovacic B, Wyrzucki AM, Gish GD, Cerny-Reiterer S, Koide A, Beug H, Pawson T, Valent P, Koide S, Superti-Furga G (2011) Targeting the SH2-kinase interface in Bcr-Abl inhibits leukemogenesis. Cell 147(2):306–319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Grutsch S, Bruschweiler S, Tollinger M (2016) NMR methods to study dynamic allostery. PLoS Comput Biol 12(3):e1004620

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Gunasekaran K, Ma B, Nussinov R (2004) Is allostery an intrinsic property of all dynamic proteins? Proteins 57(3):433–443

    Article  CAS  PubMed  Google Scholar 

  78. Guo J, Zhou HX (2016) Protein allostery and conformational dynamics. Chem Rev 116(11):6503–6515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Halabi N, Rivoire O, Leibler S, Ranganathan R (2009) Protein sectors: evolutionary units of three-dimensional structure. Cell 138(4):774–786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Hansia P, Ghosh A, Vishveshwara S (2009) Ligand dependent intra and inter subunit communication in human tryptophanyl tRNA synthetase as deduced from the dynamics of structure networks. Mol BioSyst 5(12):1860–1872

    Article  CAS  PubMed  Google Scholar 

  81. Hantschel O (2012) Structure, regulation, signaling, and targeting of abl kinases in cancer. Genes Cancer 3(5-6):436–446

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJ, Stokoe D, Gloor SL, Vigers G, Morales T, Aliagas I, Liu B, Sideris S, Hoeflich KP, Jaiswal BS, Seshagiri S, Koeppen H, Belvin M, Friedman LS, Malek S (2010) RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464(7287):431–435

    Article  CAS  PubMed  Google Scholar 

  83. Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, Hussain J, Reis-Filho JS, Springer CJ, Pritchard C, Marais R (2010) Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140(2):209–221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Heinrich T, Gradler U, Bottcher H, Blaukat A, Shutes A (2010) Allosteric IGF-1R Inhibitors. ACS Med Chem Lett 1(5):199–203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hilser VJ, Wrabl JO, Motlagh HN (2012) Structural and energetic basis of allostery. Annu Rev Biophys 41:585–609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hindie V, Stroba A, Zhang H, Lopez-Garcia LA, Idrissova L, Zeuzem S, Hirschberg D, Schaeffer F, Jorgensen TJ, Engel M, Alzari PM, Biondi RM (2009) Structure and allosteric effects of low-molecular-weight activators on the protein kinase PDK1. Nat Chem Biol 5(10):758–764

    Article  CAS  PubMed  Google Scholar 

  87. Holderfield M, Nagel TE, Stuart DD (2014) Mechanism and consequences of RAF kinase activation by small-molecule inhibitors. Br J Cancer 111(4):640–645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Hsu YH, Traugh JA (2010) Reciprocally coupled residues crucial for protein kinase Pak2 activity calculated by statistical coupling analysis. PLoS One 5(3):e9455

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Huang C, Kalodimos CG (2017) Structures of large protein complexes determined by nuclear magnetic resonance spectroscopy. Annu Rev Biophys 46:317–336

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  91. 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(Database issue):D663–D669

    Article  CAS  PubMed  Google Scholar 

  92. Iacob RE, Zhang J, Gray NS, Engen JR (2011) Allosteric interactions between the myristate- and ATP-site of the Abl kinase. PLoS One 6(1):e15929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Jahnke W, Grotzfeld RM, Pelle X, Strauss A, Fendrich G, Cowan-Jacob SW, Cotesta S, Fabbro D, Furet P, Mestan J, Marzinzik AL (2010) Binding or bending: distinction of allosteric Abl kinase agonists from antagonists by an NMR-based conformational assay. J Am Chem Soc 132(20):7043–7048

    Article  CAS  PubMed  Google Scholar 

  94. James KA, Verkhivker GM (2014) Structure-based network analysis of activation mechanisms in the ErbB family of receptor tyrosine kinases: the regulatory spine residues are global mediators of structural stability and allosteric interactions. PLoS One 9(11):46

    Article  CAS  Google Scholar 

  95. Jeon J, Nam HJ, Choi YS, Yang JS, Hwang J, Kim S (2011) Molecular evolution of protein conformational changes revealed by a network of evolutionarily coupled residues. Mol Biol Evol 28(9):2675–2685

    Article  CAS  PubMed  Google Scholar 

  96. Jiang Y, Kalodimos CG (2017) NMR Studies of Large Proteins. J Mol Biol 429(17):2667–2676

    Article  CAS  PubMed  Google Scholar 

  97. Jura N, Zhang X, Endres NF, Seeliger MA, Schindler T, Kuriyan J (2011) Catalytic control in the EGF receptor and its connection to general kinase regulatory mechanisms. Mol Cell 42(1):9–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kalbitzer HR, Rosnizeck IC, Munte CE, Narayanan SP, Kropf V, Spoerner M (2013) Intrinsic allosteric inhibition of signaling proteins by targeting rare interaction states detected by high-pressure NMR spectroscopy. Angew Chem Int Ed Eng 52(52):14242–14246

    Article  CAS  Google Scholar 

  99. Kalodimos CG (2011) NMR reveals novel mechanisms of protein activity regulation. Protein Sci 20(5):773–782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kalodimos CG (2012) Protein function and allostery: a dynamic relationship. Ann N Y Acad Sci 1260:81–86

    Article  CAS  PubMed  Google Scholar 

  101. Kay LE (2016) New views of functionally dynamic proteins by solution NMR spectroscopy. J Mol Biol 428(2 Pt A):323–331

    Article  CAS  PubMed  Google Scholar 

  102. Kaya C, Armutlulu A, Ekesan S, Haliloglu T (2013) MCPath: Monte Carlo path generation approach to predict likely allosteric pathways and functional residues. Nucleic Acids Res 41(Web Server issue):W249–W255

    Article  PubMed  PubMed Central  Google Scholar 

  103. Kern D, Zuiderweg ER (2003) The role of dynamics in allosteric regulation. Curr Opin Struct Biol 13(6):748–757

    Article  CAS  PubMed  Google Scholar 

  104. Kidd BA, Baker D, Thomas WE (2009) Computation of conformational coupling in allosteric proteins. PLoS Comput Biol 5(8):e1000484

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Kim C, Cheng CY, Saldanha SA, Taylor SS (2007) PKA-I holoenzyme structure reveals a mechanism for cAMP-dependent activation. Cell 130(6):1032–1043

    Article  CAS  PubMed  Google Scholar 

  106. Kornev AP, Taylor SS (2015) Dynamics-driven allostery in protein kinases. Trends Biochem Sci 40(11):628–647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kornev AP, Taylor SS, Ten Eyck LF (2008) A helix scaffold for the assembly of active protein kinases. Proc Natl Acad Sci U S A 105(38):14377–14382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Korzhnev DM, Kay LE (2008) Probing invisible, low-populated States of protein molecules by relaxation dispersion NMR spectroscopy: an application to protein folding. Acc Chem Res 41(3):442–451

    Article  CAS  PubMed  Google Scholar 

  109. Koshland DE Jr (1998) Conformational changes: how small is big enough? Nat Med 4(10):1112–1114

    Article  CAS  PubMed  Google Scholar 

  110. La Sala G, Decherchi S, De Vivo M, Rocchia W (2017) Allosteric communication networks in proteins revealed through pocket crosstalk analysis. ACS Cent Sci 3(9):949–960

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Lake EW, Muretta JM, Thompson AR, Rasmussen DM, Majumdar A, Faber EB, Ruff EF, Thomas DD, Levinson NM (2018) Quantitative conformational profiling of kinase inhibitors reveals origins of selectivity for Aurora kinase activation states. Proc Natl Acad Sci U S A. https://doi.org/10.1073/pnas.1811158115

    Article  CAS  Google Scholar 

  112. Lamontanara AJ, Georgeon S, Tria G, Svergun DI, Hantschel O (2014) The SH2 domain of Abl kinases regulates kinase autophosphorylation by controlling activation loop accessibility. Nat Commun 5:5470

    Article  PubMed  Google Scholar 

  113. Laughlin JD, Nwachukwu JC, Figuera-Losada M, Cherry L, Nettles KW, LoGrasso PV (2012) Structural mechanisms of allostery and autoinhibition in JNK family kinases. Structure 20(12):2174–2184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Lee BC, Park K, Kim D (2008) Analysis of the residue-residue coevolution network and the functionally important residues in proteins. Proteins 72(3):863–872

    Article  CAS  PubMed  Google Scholar 

  115. Lee BJ, Shah NP (2017) Identification and characterization of activating ABL1 1b kinase mutations: impact on sensitivity to ATP-competitive and allosteric ABL1 inhibitors. Leukemia 31(5):1096–1107

    Article  CAS  PubMed  Google Scholar 

  116. Lemmon MA (2009) Ligand-induced ErbB receptor dimerization. Exp Cell Res 315(4):638–648

    Article  CAS  PubMed  Google Scholar 

  117. Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141(7):1117–1134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Levinson NM (2018) The multifaceted allosteric regulation of Aurora kinase A. Biochem J 475(12):2025–2042

    Article  CAS  PubMed  Google Scholar 

  119. Li C, Ma N, Wang Y, Chen G (2014) Molecular dynamics simulation studies on the positive cooperativity of the Kemptide substrate with protein kinase A induced by the ATP ligand. J Phys Chem B 118(5):1273–1287

    Article  CAS  PubMed  Google Scholar 

  120. Lindsley CW, Zhao Z, Leister WH, Robinson RG, Barnett SF, Defeo-Jones D, Jones RE, Hartman GD, Huff JR, Huber HE, Duggan ME (2005) Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. Bioorg Med Chem Lett 15(3):761–764

    Article  CAS  PubMed  Google Scholar 

  121. Lisi GP, East KW, Batista VS, Loria JP (2017) Altering the allosteric pathway in IGPS suppresses millisecond motions and catalytic activity. Proc Natl Acad Sci U S A 114(17):E3414–e3423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lisi GP, Loria JP (2016) Solution NMR spectroscopy for the study of enzyme allostery. Chem Rev 116(11):6323–6369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Lisi GP, Loria JP (2017) Allostery in enzyme catalysis. Curr Opin Struct Biol 47:123–130

    Article  CAS  PubMed  Google Scholar 

  124. Lisi GP, Manley GA, Hendrickson H, Rivalta I, Batista VS, Loria JP (2016) Dissecting dynamic allosteric pathways using chemically related small-molecule activators. Structure 24(7):1155–1166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Lockless SW, Ranganathan R (1999) Evolutionarily conserved pathways of energetic connectivity in protein families. Science 286(5438):295–299

    Article  CAS  PubMed  Google Scholar 

  126. Ma B, Tsai CJ, Haliloglu T, Nussinov R (2011) Dynamic allostery: linkers are not merely flexible. Structure 19(7):907–917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Ma J (2005) Usefulness and limitations of normal mode analysis in modeling dynamics of biomolecular complexes. Structure 13(3):373–380

    Article  CAS  PubMed  Google Scholar 

  128. Marino Buslje C, Teppa E, Di Domenico T, Delfino JM, Nielsen M (2010) Networks of high mutual information define the structural proximity of catalytic sites: implications for catalytic residue identification. PLoS Comput Biol 6(11):e1000978

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Martin LC, Gloor GB, Dunn SD, Wahl LM (2005) Using information theory to search for co-evolving residues in proteins. Bioinformatics 21(22):4116–4124

    Article  CAS  PubMed  Google Scholar 

  130. Martin MP, Alam R, Betzi S, Ingles DJ, Zhu JY, Schonbrunn E (2012) A novel approach to the discovery of small-molecule ligands of CDK2. ChemBioChem 13(14):2128–2136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Mattmann ME, Stoops SL, Lindsley CW (2011) Inhibition of Akt with small molecules and biologics: historical perspective and current status of the patent landscape. Expert Opin Ther Pat 21(9):1309–1338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. McClendon CL, Friedland G, Mobley DL, Amirkhani H, Jacobson MP (2009) Quantifying correlations between allosteric sites in thermodynamic ensembles. J Chem Theory Comput 5(9):2486–2502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. McLaughlin RN Jr, Poelwijk FJ, Raman A, Gosal WS, Ranganathan R (2012) The spatial architecture of protein function and adaptation. Nature 491(7422):138–142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. McLeish TC, Rodgers TL, Wilson MR (2013) Allostery without conformation change: modelling protein dynamics at multiple scales. Phys Biol 10(5):056004

    Article  CAS  PubMed  Google Scholar 

  135. Meharena HS, Chang P, Keshwani MM, Oruganty K, Nene AK, Kannan N, Taylor SS, Kornev AP (2013) Deciphering the structural basis of eukaryotic protein kinase regulation. PLoS Biol 11(10):e1001680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Ming D, Wall ME (2005) Quantifying allosteric effects in proteins. Proteins 59(4):697–707

    Article  CAS  PubMed  Google Scholar 

  137. Ming D, Wall ME (2006) Interactions in native binding sites cause a large change in protein dynamics. J Mol Biol 358(1):213–223

    Article  CAS  PubMed  Google Scholar 

  138. Mitternacht S, Berezovsky IN (2011) Binding leverage as a molecular basis for allosteric regulation. PLoS Comput Biol 7(9):e1002148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Monod J, Wyman J, Changeux JP (1965) ON the nature of allosteric transitions: a plausible model. J Mol Biol 12:88–118

    Article  CAS  PubMed  Google Scholar 

  140. Morcos F, Pagnani A, Lunt B, Bertolino A, Marks DS, Sander C, Zecchina R, Onuchic JN, Hwa T, Weigt M (2011) Direct-coupling analysis of residue coevolution captures native contacts across many protein families. Proc Natl Acad Sci U S A 108(49):E1293–E1301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Motlagh HN, Wrabl JO, Li J, Hilser VJ (2014) The ensemble nature of allostery. Nature 508(7496):331–339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Munte CE, Beck Erlach M, Kremer W, Koehler J, Kalbitzer HR (2013) Distinct conformational states of the Alzheimer beta-amyloid peptide can be detected by high-pressure NMR spectroscopy. Angew Chem Int Ed Eng 52(34):8943–8947

    Article  CAS  Google Scholar 

  143. Nagar B, Hantschel O, Seeliger M, Davies JM, Weis WI, Superti-Furga G, Kuriyan J (2006) Organization of the SH3-SH2 unit in active and inactive forms of the c-Abl tyrosine kinase. Mol Cell 21(6):787–798

    Article  CAS  PubMed  Google Scholar 

  144. Nagar B, Hantschel O, Young MA, Scheffzek K, Veach D, Bornmann W, Clarkson B, Superti-Furga G, Kuriyan J (2003) Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell 112(6):859–871

    Article  CAS  PubMed  Google Scholar 

  145. Nesmelova IV, Ermakova E, Daragan VA, Pang M, Menendez M, Lagartera L, Solis D, Baum LG, Mayo KH (2010) Lactose binding to galectin-1 modulates structural dynamics, increases conformational entropy, and occurs with apparent negative cooperativity. J Mol Biol 397(5):1209–1230

    Article  CAS  PubMed  Google Scholar 

  146. Nishi H, Hashimoto K, Panchenko AR (2011) Phosphorylation in protein-protein binding: effect on stability and function. Structure 19(12):1807–1815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Nussinov R (2012) How do dynamic cellular signals travel long distances? Mol BioSyst 8(1):22–26

    Article  CAS  PubMed  Google Scholar 

  148. Nussinov R, Ma B, Tsai CJ, Csermely P (2013a) Allosteric conformational barcodes direct signaling in the cell. Structure 21(9):1509–1521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Nussinov R, Tsai CJ (2013) Allostery in disease and in drug discovery. Cell 153(2):293–305

    Article  CAS  PubMed  Google Scholar 

  150. Nussinov R, Tsai CJ (2015) Allostery without a conformational change? Revisiting the paradigm. Curr Opin Struct Biol 30:17–24

    Article  CAS  PubMed  Google Scholar 

  151. Nussinov R, Tsai CJ, Csermely P (2011) Allo-network drugs: harnessing allostery in cellular networks. Trends Pharmacol Sci 32(12):686–693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Nussinov R, Tsai CJ, Ma B (2013b) The underappreciated role of allostery in the cellular network. Annu Rev Biophys 42:169–189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Nussinov R, Tsai CJ, Xin F, Radivojac P (2012) Allosteric post-translational modification codes. Trends Biochem Sci 37(10):447–455

    Article  CAS  PubMed  Google Scholar 

  154. Oruganty K, Kannan N (2012) Design principles underpinning the regulatory diversity of protein kinases. Philos Trans R Soc Lond Ser B Biol Sci 367(1602):2529–2539

    Article  CAS  Google Scholar 

  155. Owen GR, Stoychev S, Achilonu I, Dirr HW (2014) Phosphorylation- and nucleotide-binding-induced changes to the stability and hydrogen exchange patterns of JNK1beta1 provide insight into its mechanisms of activation. J Mol Biol 426(21):3569–3589

    Article  CAS  PubMed  Google Scholar 

  156. Panjarian S, Iacob RE, Chen S, Engen JR, Smithgall TE (2013) Structure and dynamic regulation of Abl kinases. J Biol Chem 288(8):5443–5450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Panjkovich A, Daura X (2014) PARS: a web server for the prediction of Protein Allosteric and Regulatory Sites. Bioinformatics 30(9):1314–1315

    Article  CAS  PubMed  Google Scholar 

  158. Popovych N, Sun S, Ebright RH, Kalodimos CG (2006) Dynamically driven protein allostery. Nat Struct Mol Biol 13(9):831–838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N (2010) RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464(7287):427–430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Rader AJ, Brown SM (2011) Correlating allostery with rigidity. Mol BioSyst 7(2):464–471

    Article  CAS  PubMed  Google Scholar 

  161. Rastelli G, Anighoro A, Chripkova M, Carrassa L, Broggini M (2014) Structure-based discovery of the first allosteric inhibitors of cyclin-dependent kinase 2. Cell Cycle 13(14):2296–2305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Reddy EP, Aggarwal AK (2012) The ins and outs of bcr-abl inhibition. Genes Cancer 3(5-6):447–454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Rice KD, Aay N, Anand NK, Blazey CM, Bowles OJ, Bussenius J, Costanzo S, Curtis JK, Defina SC, Dubenko L, Engst S, Joshi AA, Kennedy AR, Kim AI, Koltun ES, Lougheed JC, Manalo JC, Martini JF, Nuss JM, Peto CJ, Tsang TH, Yu P, Johnston S (2012) Novel carboxamide-based allosteric MEK inhibitors: discovery and optimization efforts toward XL518 (GDC-0973). ACS Med Chem Lett 3(5):416–421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Rivalta I, Sultan MM, Lee NS, Manley GA, Loria JP, Batista VS (2012) Allosteric pathways in imidazole glycerol phosphate synthase. Proc Natl Acad Sci U S A 109(22):E1428–E1436

    Article  PubMed  PubMed Central  Google Scholar 

  165. Rosenzweig R, Kay LE (2014) Bringing dynamic molecular machines into focus by methyl-TROSY NMR. Annu Rev Biochem 83:291–315

    Article  CAS  PubMed  Google Scholar 

  166. Roskoski R Jr (2004) Src protein-tyrosine kinase structure and regulation. Biochem Biophys Res Commun 324(4):1155–1164

    Article  CAS  PubMed  Google Scholar 

  167. Roskoski R Jr (2015a) A historical overview of protein kinases and their targeted small molecule inhibitors. Pharmacol Res 100:1–23

    Article  CAS  PubMed  Google Scholar 

  168. Roskoski R Jr (2015b) Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors. Pharmacol Res 94:9–25

    Article  CAS  PubMed  Google Scholar 

  169. Roskoski R Jr (2016) Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol Res 103:26–48

    Article  CAS  PubMed  Google Scholar 

  170. Rudolph J, Xiao Y, Pardi A, Ahn NG (2015) Slow inhibition and conformation selective properties of extracellular signal-regulated kinase 1 and 2 inhibitors. Biochemistry 54(1):22–31

    Article  CAS  PubMed  Google Scholar 

  171. Ruff EF, Muretta JM, Thompson AR, Lake EW, Cyphers S, Albanese SK, Hanson SM, Behr JM, Thomas DD, Chodera JD, Levinson NM (2018) A dynamic mechanism for allosteric activation of Aurora kinase A by activation loop phosphorylation. eLife 7. https://doi.org/10.7554/eLife.32766

  172. Ruschak AM, Kay LE (2012) Proteasome allostery as a population shift between interchanging conformers. Proc Natl Acad Sci U S A 109(50):E3454–E3462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Saleh T, Rossi P, Kalodimos CG (2017) Atomic view of the energy landscape in the allosteric regulation of Abl kinase. Nat Struct Mol Biol 24(11):893–901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Schneider EV, Bottcher J, Huber R, Maskos K, Neumann L (2013) Structure-kinetic relationship study of CDK8/CycC specific compounds. Proc Natl Acad Sci U S A 110(20):8081–8086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Schoepfer J, Jahnke W, Berellini G, Buonamici S, Cotesta S, Cowan-Jacob SW, Dodd S, Drueckes P, Fabbro D, Gabriel T, Groell JM, Grotzfeld RM, Hassan AQ, Henry C, Iyer V, Jones D, Lombardo F, Loo A, Manley PW, Pelle X, Rummel G, Salem B, Warmuth M, Wylie AA, Zoller T, Marzinzik AL, Furet P (2018) Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1. J Med Chem 61(18):8120–8135

    Article  CAS  PubMed  Google Scholar 

  176. Sethi A, Eargle J, Black AA, Luthey-Schulten Z (2009) Dynamical networks in tRNA:protein complexes. Proc Natl Acad Sci U S A 106(16):6620–6625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Sethi A, Tian J, Derdeyn CA, Korber B, Gnanakaran S (2013) A mechanistic understanding of allosteric immune escape pathways in the HIV-1 envelope glycoprotein. PLoS Comput Biol 9(5):e1003046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Shaw AS, Kornev AP, Hu J, Ahuja LG, Taylor SS (2014) Kinases and pseudokinases: lessons from RAF. Mol Cell Biol 34(9):1538–1546

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. 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(D1):D527–D535

    Article  CAS  PubMed  Google Scholar 

  180. Shi L, Kay LE (2014) Tracing an allosteric pathway regulating the activity of the HslV protease. Proc Natl Acad Sci U S A 111(6):2140–2145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. 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 

  182. Simard JR, Kluter S, Grutter C, Getlik M, Rabiller M, Rode HB, Rauh D (2009) A new screening assay for allosteric inhibitors of cSrc. Nat Chem Biol 5(6):394–396

    Article  CAS  PubMed  Google Scholar 

  183. Simonetti FL, Teppa E, Chernomoretz A, Nielsen M, Marino Buslje C (2013) MISTIC: mutual information server to infer coevolution. Nucleic Acids Res 41(Web Server issue):W8–W14

    Article  PubMed  PubMed Central  Google Scholar 

  184. Smock RG, Gierasch LM (2009) Sending signals dynamically. Science 324(5924):198–203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Socolich M, Lockless SW, Russ WP, Lee H, Gardner KH, Ranganathan R (2005) Evolutionary information for specifying a protein fold. Nature 437(7058):512–518

    Article  CAS  PubMed  Google Scholar 

  186. Staus DP, Strachan RT, Manglik A, Pani B, Kahsai AW, Kim TH, Wingler LM, Ahn S, Chatterjee A, Masoudi A, Kruse AC, Pardon E, Steyaert J, Weis WI, Prosser RS, Kobilka BK, Costa T, Lefkowitz RJ (2016) Allosteric nanobodies reveal the dynamic range and diverse mechanisms of G-protein-coupled receptor activation. Nature 535(7612):448–452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. 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(1):34

    Article  CAS  Google Scholar 

  188. Stevens SY, Sanker S, Kent C, Zuiderweg ER (2001) Delineation of the allosteric mechanism of a cytidylyltransferase exhibiting negative cooperativity. Nat Struct Biol 8(11):947–952

    Article  CAS  PubMed  Google Scholar 

  189. Stock G, Hamm P (2018) A non-equilibrium approach to allosteric communication. Philos Trans R Soc Lond Ser B Biol Sci 373(1749):20170187

    Article  CAS  Google Scholar 

  190. Stockman BJ, Kothe M, Kohls D, Weibley L, Connolly BJ, Sheils AL, Cao Q, Cheng AC, Yang L, Kamath AV, Ding YH, Charlton ME (2009) Identification of allosteric PIF-pocket ligands for PDK1 using NMR-based fragment screening and 1H-15N TROSY experiments. Chem Biol Drug Des 73(2):179–188

    Article  CAS  PubMed  Google Scholar 

  191. Stolzenberg S, Michino M, LeVine MV, Weinstein H, Shi L (2016) Computational approaches to detect allosteric pathways in transmembrane molecular machines. Biochim Biophys Acta 1858(7 Pt B):1652–1662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Suel GM, Lockless SW, Wall MA, Ranganathan R (2003) Evolutionarily conserved networks of residues mediate allosteric communication in proteins. Nat Struct Biol 10(1):59–69

    Article  PubMed  CAS  Google Scholar 

  193. Swain JF, Gierasch LM (2006) The changing landscape of protein allostery. Curr Opin Struct Biol 16(1):102–108

    Article  CAS  PubMed  Google Scholar 

  194. Szilagyi 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(1):64–77

    Article  CAS  PubMed  Google Scholar 

  195. Tappan E, Chamberlin AR (2008) Activation of protein phosphatase 1 by a small molecule designed to bind to the enzyme’s regulatory site. Chem Biol 15(2):167–174

    Article  CAS  PubMed  Google Scholar 

  196. Taylor SS, Keshwani MM, Steichen JM, Kornev AP (2012) Evolution of the eukaryotic protein kinases as dynamic molecular switches. Philos Trans R Soc Lond Ser B Biol Sci 367(1602):2517–2528

    Article  CAS  Google Scholar 

  197. Taylor SS, Kim C, Cheng CY, Brown SH, Wu J, Kannan N (2008) Signaling through cAMP and cAMP-dependent protein kinase: diverse strategies for drug design. Biochim Biophys Acta 1784(1):16–26

    Article  CAS  PubMed  Google Scholar 

  198. Taylor SS, Kornev AP (2011) Protein kinases: evolution of dynamic regulatory proteins. Trends Biochem Sci 36(2):65–77

    Article  CAS  PubMed  Google Scholar 

  199. Taylor SS, Zhang P, Steichen JM, Keshwani MM, Kornev AP (2013) PKA: lessons learned after twenty years. Biochim Biophys Acta 1834(7):1271–1278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Tehver R, Chen J, Thirumalai D (2009) Allostery wiring diagrams in the transitions that drive the GroEL reaction cycle. J Mol Biol 387(2):390–406

    Article  CAS  PubMed  Google Scholar 

  201. Teppa E, Wilkins AD, Nielsen M, Buslje CM (2012) Disentangling evolutionary signals: conservation, specificity determining positions and coevolution. Implication for catalytic residue prediction. BMC Bioinf 13:235

    Article  Google Scholar 

  202. Tillier ER, Lui TW (2003) Using multiple interdependency to separate functional from phylogenetic correlations in protein alignments. Bioinformatics 19(6):750–755

    Article  CAS  PubMed  Google Scholar 

  203. Tomita N, Hayashi Y, Suzuki S, Oomori Y, Aramaki Y, Matsushita Y, Iwatani M, Iwata H, Okabe A, Awazu Y, Isono O, Skene RJ, Hosfield DJ, Miki H, Kawamoto T, Hori A, Baba A (2013) Structure-based discovery of cellular-active allosteric inhibitors of FAK. Bioorg Med Chem Lett 23(6):1779–1785

    Article  CAS  PubMed  Google Scholar 

  204. Tsai CJ, del Sol A, Nussinov R (2008) Allostery: absence of a change in shape does not imply that allostery is not at play. J Mol Biol 378(1):1–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Tsai CJ, Del Sol A, Nussinov R (2009) Protein allostery, signal transmission and dynamics: a classification scheme of allosteric mechanisms. Mol BioSyst 5(3):207–216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Tsai CJ, Nussinov R (2014) A unified view of "how allostery works". PLoS Comput Biol 10(2):e1003394

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  207. Tse A, Verkhivker GM (2015) Molecular determinants underlying binding specificities of the ABL kinase inhibitors: combining alanine scanning of binding hot spots with network analysis of residue interactions and coevolution. PLoS One 10(6):43

    Article  CAS  Google Scholar 

  208. Tse A, Verkhivker GM (2016) Exploring molecular mechanisms of paradoxical activation in the BRAF kinase dimers: atomistic simulations of conformational dynamics and modeling of allosteric communication networks and signaling pathways. PLoS One 11(11):e0166583

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  209. Tzeng SR, Kalodimos CG (2009) Dynamic activation of an allosteric regulatory protein. Nature 462(7271):368–372

    Article  CAS  PubMed  Google Scholar 

  210. Tzeng SR, Kalodimos CG (2011) Protein dynamics and allostery: an NMR view. Curr Opin Struct Biol 21(1):62–67

    Article  CAS  PubMed  Google Scholar 

  211. 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(10):3146–3165

    Article  CAS  PubMed  Google Scholar 

  212. Verkhivker GM (2017) Leveraging structural diversity and allosteric regulatory mechanisms of protein kinases in the discovery of small molecule inhibitors. Curr Med Chem 24(42):4838–4872

    CAS  PubMed  Google Scholar 

  213. Vijayabaskar MS, Vishveshwara S (2010) Interaction energy based protein structure networks. Biophys J 99(11):3704–3715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Wang J, Zhao Y, Wang Y, Huang J (2013) Molecular dynamics simulations and statistical coupling analysis reveal functional coevolution network of oncogenic mutations in the CDKN2A-CDK6 complex. FEBS Lett 587(2):136–141

    Article  CAS  PubMed  Google Scholar 

  215. Weinkam P, Pons J, Sali A (2012) Structure-based model of allostery predicts coupling between distant sites. Proc Natl Acad Sci U S A 109(13):4875–4880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. 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 

  217. White JT, Li J, Grasso E, Wrabl JO, Hilser VJ (2018) Ensemble allosteric model: energetic frustration within the intrinsically disordered glucocorticoid receptor. Philos Trans R Soc Lond Ser B Biol Sci 373(1749):20170175

    Article  CAS  Google Scholar 

  218. Whittington AC, Larion M, Bowler JM, Ramsey KM, Bruschweiler R, Miller BG (2015) Dual allosteric activation mechanisms in monomeric human glucokinase. Proc Natl Acad Sci U S A 112(37):11553–11558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Williamson MP, Kitahara R (2018) Characterization of low-lying excited states of proteins by high-pressure NMR. Biochim Biophys Acta, Proteins Proteomics. https://doi.org/10.1016/j.bbapap.2018.10.014

    Article  CAS  Google Scholar 

  220. Wrabl JO, Gu J, Liu T, Schrank TP, Whitten ST, Hilser VJ (2011) The role of protein conformational fluctuations in allostery, function, and evolution. Biophys Chem 159(1):129–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  222. Wu P, Nielsen TE, Clausen MH (2015b) FDA-approved small-molecule kinase inhibitors. Trends Pharmacol Sci 36(7):422–439

    Article  CAS  PubMed  Google Scholar 

  223. Wu WI, Voegtli WC, Sturgis HL, Dizon FP, Vigers GP, Brandhuber BJ (2010) Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition. PLoS One 5(9):e12913

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  224. Wylie AA, Schoepfer J, Jahnke W, Cowan-Jacob SW, Loo A, Furet P, Marzinzik AL, Pelle X, Donovan J, Zhu W, Buonamici S, Hassan AQ, Lombardo F, Iyer V, Palmer M, Berellini G, Dodd S, Thohan S, Bitter H, Branford S, Ross DM, Hughes TP, Petruzzelli L, Vanasse KG, Warmuth M, Hofmann F, Keen NJ, Sellers WR (2017) The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature 543(7647):733–737

    Article  CAS  PubMed  Google Scholar 

  225. Xiao Y, Lee T, Latham MP, Warner LR, Tanimoto A, Pardi A, Ahn NG (2014) Phosphorylation releases constraints to domain motion in ERK2. Proc Natl Acad Sci U S A 111(7):2506–2511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Xiao Y, Liddle JC, Pardi A, Ahn NG (2015) Dynamics of protein kinases: insights from nuclear magnetic resonance. Acc Chem Res 48(4):1106–1114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Xie T, Peng W, Liu Y, Yan C, Maki J, Degterev A, Yuan J, Shi Y (2013) Structural basis of RIP1 inhibition by necrostatins. Structure 21(3):493–499

    Article  CAS  PubMed  Google Scholar 

  228. Xie T, Saleh T, Kalodimos CG (2018) Gleevec can act as an allosteric inhibitor of ABL. Biophys J 114(3):1150–PosB59

    Article  CAS  Google Scholar 

  229. Xu F, Du P, Shen H, Hu H, Wu Q, Xie J, Yu L (2009) Correlated mutation analysis on the catalytic domains of serine/threonine protein kinases. PLoS One 4(6):e5913

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  230. Yang J, Campobasso N, Biju MP, Fisher K, Pan XQ, Cottom J, Galbraith S, Ho T, Zhang H, Hong X, Ward P, Hofmann G, Siegfried B, Zappacosta F, Washio Y, Cao P, Qu J, Bertrand S, Wang DY, Head MS, Li H, Moores S, Lai Z, Johanson K, Burton G, Erickson-Miller C, Simpson G, Tummino P, Copeland RA, Oliff A (2011) Discovery and characterization of a cell-permeable, small-molecule c-Abl kinase activator that binds to the myristoyl binding site. Chem Biol 18(2):177–186

    Article  CAS  PubMed  Google Scholar 

  231. Yang LW, Rader AJ, Liu X, Jursa CJ, Chen SC, Karimi HA, Bahar I (2006) oGNM: online computation of structural dynamics using the Gaussian Network Model. Nucleic Acids Res 34(Web Server issue):W24–W31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Yeang CH, Haussler D (2007) Detecting coevolution in and among protein domains. PLoS Comput Biol 3(11):e211

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  233. Zhang J, Adrian FJ, Jahnke W, Cowan-Jacob SW, Li AG, Iacob RE, Sim T, Powers J, Dierks C, Sun F, Guo GR, Ding Q, Okram B, Choi Y, Wojciechowski A, Deng X, Liu G, Fendrich G, Strauss A, Vajpai N, Grzesiek S, Tuntland T, Liu Y, Bursulaya B, Azam M, Manley PW, Engen JR, Daley GQ, Warmuth M, Gray NS (2010) Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature 463(7280):501–506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Zhang J, Yang PL, Gray NS (2009) Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 9(1):28–39

    Article  CAS  PubMed  Google Scholar 

  235. Zhao Y, Wang Y, Gao Y, Li G, Huang J (2015) Integrated analysis of residue coevolution and protein structures capture key protein sectors in HIV-1 proteins. PLoS One 10(2):e0117506

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  236. Zhuravlev PI, Papoian GA (2010) Protein functional landscapes, dynamics, allostery: a tortuous path towards a universal theoretical framework. Q Rev Biophys 43(3):295–332

    Article  CAS  PubMed  Google Scholar 

  237. Zorn JA, Wells JA (2010) Turning enzymes ON with small molecules. Nat Chem Biol 6(3):179–188

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Graduate Program in Computational and Data Sciences, Schmid College of Science and Technology, Chapman University, Orange, CA, USA

    Lindy Astl, Amanda Tse & Gennady M. Verkhivker

  2. Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA, USA

    Gennady M. Verkhivker

  3. Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA

    Gennady M. Verkhivker

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  1. Lindy Astl
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  2. Amanda Tse
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  3. Gennady M. Verkhivker
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Correspondence to Gennady M. Verkhivker .

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Editors and Affiliations

  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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Astl, L., Tse, A., Verkhivker, G.M. (2019). Interrogating Regulatory Mechanisms in Signaling Proteins by Allosteric Inhibitors and Activators: A Dynamic View Through the Lens of Residue Interaction Networks. 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_9

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