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Single Binding Pockets Versus Allosteric Binding

  • Kun Song
  • Jian ZhangEmail author
Protocol
  • 915 Downloads
Part of the Methods in Molecular Biology book series (MIMB, volume 1825)

Abstract

An orthosteric site is commonly viewed as the primary, functionally binding pocket on a receptor. Signal molecules, endogenous agonists, and substrates are recognized by and bind to the orthosteric site of a specific target, resulting in a biological effect. A malfunctioning active site on a crucial receptor has been confirmed as the culprit that causes many metabolic disturbances, neurologic disorders, and genetic diseases. A competitive inhibitor that has a stronger binding affinity can outcompete an orthosteric ligand. An allosteric site, which is nonoverlapping and topographically distinct from the active pocket, can emerge as a potential regulatory site on the protein surface. An allosteric modulator interacts with a specific binding site, affecting the atoms of nearby residues, thus eliciting a series of conformational changes in the residues at the active site through propagation pathways. Allosteric regulation can potentiate or inhibit function instead of blocking it, and this is a promising strategy for drug design. In this chapter, we describe the tools and protocols for allosteric site analysis and allosteric ligand design.

Key words

Allostery Allosteric site Orthosteric site Drug design Computational methods 

References

  1. 1.
    Changeux J-P, Christopoulos A (2016) Allosteric modulation as a unifying mechanism for receptor function and regulation. Cell 166(5):1084–1102CrossRefGoogle Scholar
  2. 2.
    Lu S, Li S, Zhang J (2014) Harnessing allostery: a novel approach to drug discovery. Med Res Rev 34(6):1242–1285CrossRefGoogle Scholar
  3. 3.
    Liu J, Nussinov R (2016) Allostery: an overview of its history, concepts, methods, and applications. PLoS Comput Biol 12(6):e1004966CrossRefGoogle Scholar
  4. 4.
    Kar G, Keskin O, Gursoy A, Nussinov R (2010) Allostery and population shift in drug discovery. Curr Opin Pharmacol 10:715–722CrossRefGoogle Scholar
  5. 5.
    Lu S, Huang W, Zhang J (2014) Recent computational advances in the identification of allosteric sites in proteins. Drug Discov Today 19:1595–1600CrossRefGoogle Scholar
  6. 6.
    Motlagh HN, Wrabl JO, Li J, Hilser VJ (2014) The ensemble nature of allostery. Nature 508:331–339CrossRefGoogle Scholar
  7. 7.
    Nussinov R (2012) Allosteric modulators can restore function in an amino acid neurotransmitter receptor by slightly altering intra-molecular communication pathways. Br J Pharmacol 165:2110–2112CrossRefGoogle Scholar
  8. 8.
    Hilser VJ, Wrabl JO, Motlagh HN (2012) Structural and energetic basis of allostery. Annu Rev Biophys 41:585–609CrossRefGoogle Scholar
  9. 9.
    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 40:30–39CrossRefGoogle Scholar
  10. 10.
    Tsai C-J, Nussinov R (2014) A unified view of “how allostery works”. PLoS Comput Biol 10(2):e1003394CrossRefGoogle Scholar
  11. 11.
    Reynolds KA, McLaughlin RN, Ranganathan R (2011) Hotspots for allosteric regulation on protein surfaces. Cell 147(7):1564–1575CrossRefGoogle Scholar
  12. 12.
    Nussinov R, Tsai C-J (2014) Unraveling structural mechanisms of allosteric drug action. Trends Pharmacol Sci 35:256–264CrossRefGoogle Scholar
  13. 13.
    Lu S, Huang W, Wang Q, Shen Q, Li S, Nussinov R, Zhang J (2014) The structural basis of ATP as an allosteric modulator. PLoS Comput Biol 10:e1003831CrossRefGoogle Scholar
  14. 14.
    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 116:6370–6390CrossRefGoogle Scholar
  15. 15.
    Nussinov R, Tsai C-J (2013) Allostery in disease and in drug discovery. Cell 153:293–305CrossRefGoogle Scholar
  16. 16.
    Wenthur CJ, Gentry PR, Mathews TP, Lindsley CW (2014) Drugs for allosteric sites on receptors. Annu Rev Pharmacol Toxicol 54:165–184CrossRefGoogle Scholar
  17. 17.
    Flor PJ, Acher FC (2012) Orthosteric versus allosteric GPCR activation: the great challenge of group-III mGluRs. Biochem Pharmacol 84(4):414–424CrossRefGoogle Scholar
  18. 18.
    De Smet F, Christopoulos A, Carmeliet P (2014) Allosteric targeting of receptor tyrosine kinases. Nat Biotechnol 32:1113–1120CrossRefGoogle Scholar
  19. 19.
    Nussinov R, Tsai C-J (2012) The different ways through which specificity works in orthosteric and allosteric drugs. Curr Pharm Des 18:1311–1316CrossRefGoogle Scholar
  20. 20.
    Nussinov R, Tsai C-J (2014) The design of covalent allosteric drugs. Annu Rev Pharmacol Toxicol 55:249–267CrossRefGoogle Scholar
  21. 21.
    Wootten D, Christopoulos A, Sexton PM (2013) Emerging paradigms in GPCR allostery: implications for drug discovery. Nat Rev Drug Discov 12(8):630–644CrossRefGoogle Scholar
  22. 22.
    Jeffrey Conn P, 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(9):692–708CrossRefGoogle Scholar
  23. 23.
    Nussinov R, Tsai C-J, Ma B (2013) The underappreciated role of allostery in the cellular network. Annu Rev Biophys 42:169–189CrossRefGoogle Scholar
  24. 24.
    Guarnera E, Berezovsky IN (2016) Allosteric sites remote control in regulation of protein activity. Curr Opin Struct Biol 37:1–8CrossRefGoogle Scholar
  25. 25.
    Dokholyan NV (2016) Controlling allosteric networks in proteins. Chem Rev 116:6463–6487CrossRefGoogle Scholar
  26. 26.
    Feher VA, Durrant JD, Van Wart AT, Amaro RE (2014) Computational approaches to mapping allosteric pathways. Curr Opin Struct Biol 25:98–103CrossRefGoogle Scholar
  27. 27.
    Hertig S, Latorraca NR, Dror RO (2016) Revealing atomic-level mechanisms of protein allostery with molecular dynamics simulations. PLoS Comput Biol 12(6):e1004746CrossRefGoogle Scholar
  28. 28.
    Yao X, Skjærven L, Grant BJ (2016) Rapid characterization of allosteric networks with ensemble normal mode analysis. J Phys Chem B 120:8276–8288CrossRefGoogle Scholar
  29. 29.
    Ribeiro AAST, Ortiz V (2016) A chemical perspective on allostery. Chem Rev 116:6488–6502CrossRefGoogle Scholar
  30. 30.
    Schueler-Furman O, Wodak SJ (2016) Computational approaches to investigating allostery. Curr Opin Struct Biol 41:159–171CrossRefGoogle Scholar
  31. 31.
    Sumbul F, Acuner-Ozbabacan SE, Haliloglu T (2015) Allosteric dynamic control of binding. Biophys J 109(6):1190–1201CrossRefGoogle Scholar
  32. 32.
    Huang W, Lu S, Huang Z, Liu X, Mou L, Luo Y, Zhao Y, Liu Y, Chen Z, Hou T, Zhang J (2013) Allosite: a method for predicting allosteric sites. Bioinformatics 29(18):2357–2359CrossRefGoogle Scholar
  33. 33.
    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.  https://doi.org/10.1093/nar/gkt460CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Panjkovich A, Daura X (2014) PARS: a web server for the prediction of protein allosteric and regulatory sites. Bioinformatics 30:1314–1315.  https://doi.org/10.1093/bioinformatics/btu002CrossRefPubMedGoogle Scholar
  35. 35.
    Clarke D, Sethi A, Li S, Kumar S, Chang RWF, Chen J, Gerstein M (2016) Identifying allosteric hotspots with dynamics: application to inter- and intra-species conservation. Structure 24:826–837CrossRefGoogle Scholar
  36. 36.
    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:W249–W255CrossRefGoogle Scholar
  37. 37.
    Weinkama P, Ponsb J, Salia A (2012) Structure-based model of allostery predicts coupling between distant sites. Proc Natl Acad Sci U S A 109:4875–4880CrossRefGoogle Scholar
  38. 38.
    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 (2015) ASD v3.0: unraveling allosteric regulation with structural mechanisms and biological networks. Nucleic Acids Res 44(D1):D527–D535.  https://doi.org/10.1093/nar/gkv902CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Kanehisa M, Goto S, Sato Y, Furumichi M, Tanabe M (2012) KEGG for integration and interpretation of large-scale molecular data sets. Nucleic Acids Res 40:D109–D114CrossRefGoogle Scholar
  40. 40.
    Kanehisa M, Goto S, Sato Y, Kawashima M, Furumichi M, Tanabe M (2014) Data, information, knowledge and principle: back to metabolism in KEGG. Nucleic Acids Res 42:D199–D205CrossRefGoogle Scholar
  41. 41.
    Huang W, Wang G, Shen Q, Liu X, Lu S, Geng L, Huang Z, Zhang J (2015) ASBench: benchmarking sets for allosteric discovery. Bioinformatics 31(15):2598–2600CrossRefGoogle Scholar
  42. 42.
    Gao M, Skolnick J (2013) APoc: large-scale identification of similar protein pockets. Bioinformatics 29(5):597–604CrossRefGoogle Scholar
  43. 43.
    Mitternacht S, Igor NB (2011) A geometry-based generic predictor for catalytic and allosteric sites. Protein Eng Des Sel 24(4):405–409CrossRefGoogle Scholar
  44. 44.
    McCarthy M, Prakash P, Gorfe AA (2016) Computational allosteric ligand binding site identification on Ras proteins. Acta Biochim Biophys Sin 48(1):3–10PubMedGoogle Scholar
  45. 45.
    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–D669CrossRefGoogle Scholar
  46. 46.
    Wang Q, Zheng M, Huang Z, Liu X, Zhou H, Chen Y, Shi T, Zhang J (2012) Toward understanding the molecular basis for chemical allosteric modulator design. J Mol Graph Model 38:324–333CrossRefGoogle Scholar
  47. 47.
    Li S, Shen Q, Su M, Liu X, Lu S, Chen Z, Wang R, Zhang J (2016) Alloscore: a tool for predicting allosteric ligand-protein interaction. Bioinformatics 31:1574–1576.  https://doi.org/10.1093/bioinformatics/btw036CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of EducationShanghai Jiao-Tong University School of MedicineShanghaiChina

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