Allosteric Modulation as a Unifying Mechanism for Receptor Function and Regulation

Cell

Volumn 166, Issue 5, 2016, Pages 1084-1102

  Changeux, Jean Pierre ^a   Christopoulos, Arthur ^b  

^a INSTITUT PASTEUR   (France)

^b MONASH UNIVERSITY   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

CELL NUCLEUS RECEPTOR; G PROTEIN COUPLED RECEPTOR; HORMONE RECEPTOR; ION CHANNEL; MONOMER; OLIGOMER; PROTEIN TYROSINE KINASE; CELL RECEPTOR; LIGAND; LIGAND GATED ION CHANNEL;

ALLOSTERISM; BINDING SITE; CRYSTAL STRUCTURE; LIGAND BINDING; MOLECULAR DYNAMICS; OLIGOMERIZATION; PRIORITY JOURNAL; PROTEIN CONFORMATION; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; AGONISTS; ALLOSTERIC SITE; ANIMAL; CHEMICAL MODEL; CHEMISTRY; DISEASES; DRUG DESIGN; GENETICS; HUMAN; MUTATION; PROTEIN MULTIMERIZATION;

ALLOSTERIC REGULATION; ALLOSTERIC SITE; ANIMALS; DISEASE; DRUG DESIGN; HUMANS; LIGAND-GATED ION CHANNELS; LIGANDS; MODELS, CHEMICAL; MUTATION; PROTEIN CONFORMATION; PROTEIN MULTIMERIZATION; RECEPTOR PROTEIN-TYROSINE KINASES; RECEPTORS, CYTOPLASMIC AND NUCLEAR; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION;

EID: 84983803055     PISSN: 00928674     EISSN: 10974172     Source Type: Journal    
DOI: 10.1016/j.cell.2016.08.015     Document Type: Review

References (219)

1. Agnati, L.F., Guidolin, D., Cervetto, C., Borroto-Escuela, D.O., Fuxe, K., Role of iso-receptors in receptor-receptor interactions with a focus on dopamine iso-receptor complexes. Rev. Neurosci. 27 (2016), 1–25.
2. Althoff, T., Hibbs, R.E., Banerjee, S., Gouaux, E., X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors. Nature 512 (2014), 333–337.
3. Andersen, R.J., Mawji, N.R., Wang, J., Wang, G., Haile, S., Myung, J.K., Watt, K., Tam, T., Yang, Y.C., Bañuelos, C.A., et al. Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor. Cancer Cell 17 (2010), 535–546.
4. Arkhipov, A., Shan, Y., Das, R., Endres, N.F., Eastwood, M.P., Wemmer, D.E., Kuriyan, J., Shaw, D.E., Architecture and membrane interactions of the EGF receptor. Cell 152 (2013), 557–569.
5. Arnaout, M.A., Mahalingam, B., Xiong, J.P., Integrin structure, allostery, and bidirectional signaling. Annu. Rev. Cell Dev. Biol. 21 (2005), 381–410.
6. Arnold, L.A., Estébanez-Perpiñá, E., Togashi, M., Jouravel, N., Shelat, A., McReynolds, A.C., Mar, E., Nguyen, P., Baxter, J.D., Fletterick, R.J., et al. Discovery of small molecule inhibitors of the interaction of the thyroid hormone receptor with transcriptional coregulators. J. Biol. Chem. 280 (2005), 43048–43055.
7. Azzi, M., Charest, P.G., Angers, S., Rousseau, G., Kohout, T., Bouvier, M., Piñeyro, G., Beta-arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors. Proc. Natl. Acad. Sci. USA 100 (2003), 11406–11411.
8. Baconguis, I., Gouaux, E., Structural plasticity and dynamic selectivity of acid-sensing ion channel-spider toxin complexes. Nature 489 (2012), 400–405.
9. Baconguis, I., Hattori, M., Gouaux, E., Unanticipated parallels in architecture and mechanism between ATP-gated P2X receptors and acid sensing ion channels. Curr. Opin. Struct. Biol. 23 (2013), 277–284.
10. Bertrand, D., Gopalakrishnan, M., Allosteric modulation of nicotinic acetylcholine receptors. Biochem. Pharmacol. 74 (2007), 1155–1163.
11. Bhaskar, V., Goldfine, I.D., Bedinger, D.H., Lau, A., Kuan, H.F., Gross, L.M., Handa, M., Maddux, B.A., Watson, S.R., Zhu, S., et al. A fully human, allosteric monoclonal antibody that activates the insulin receptor and improves glycemic control. Diabetes 61 (2012), 1263–1271.
12. Black, J., Drugs from emasculated hormones: the principle of syntopic antagonism. Science 245 (1989), 486–493.
13. Blume-Jensen, P., Hunter, T., Oncogenic kinase signalling. Nature 411 (2001), 355–365.
14. Bocquet, N., Nury, H., Baaden, M., Le Poupon, C., Changeux, J.P., Delarue, M., Corringer, P.J., X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation. Nature 457 (2009), 111–114.
15. Bokoch, M.P., Zou, Y., Rasmussen, S.G., Liu, C.W., Nygaard, R., Rosenbaum, D.M., Fung, J.J., Choi, H.J., Thian, F.S., Kobilka, T.S., et al. Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor. Nature 463 (2010), 108–112.
16. Bono, F., De Smet, F., Herbert, C., De Bock, K., Georgiadou, M., Fons, P., Tjwa, M., Alcouffe, C., Ny, A., Bianciotto, M., et al. Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties. Cancer Cell 23 (2013), 477–488.
17. Bouvier, M., Oligomerization of G-protein-coupled transmitter receptors. Nat. Rev. Neurosci. 2 (2001), 274–286.
18. Bovet, D., The relationship between isosterism and competitive phenomena in the field of drug therapy of the autonomic nervous system and that of the neuromuscular transmission. Nobel Lectures, Physiology or Medicine 1942–1962, 1964, Elsevier, 552–578.
19. Brannigan, G., Hénin, J., Law, R., Eckenhoff, R., Klein, M.L., Embedded cholesterol in the nicotinic acetylcholine receptor. Proc. Natl. Acad. Sci. USA 105 (2008), 14418–14423.
20. Buck, L., Axel, R., A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell 65 (1991), 175–187.
21. Burgess, A.W., Cho, H.S., Eigenbrot, C., Ferguson, K.M., Garrett, T.P., Leahy, D.J., Lemmon, M.A., Sliwkowski, M.X., Ward, C.W., Yokoyama, S., An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol. Cell 12 (2003), 541–552.
22. Burris, T.P., Solt, L.A., Wang, Y., Crumbley, C., Banerjee, S., Griffett, K., Lundasen, T., Hughes, T., Kojetin, D.J., Nuclear receptors and their selective pharmacologic modulators. Pharmacol. Rev. 65 (2013), 710–778.
23. Buzón, V., Carbó, L.R., Estruch, S.B., Fletterick, R.J., Estébanez-Perpiñá, E., A conserved surface on the ligand binding domain of nuclear receptors for allosteric control. Mol. Cell. Endocrinol. 348 (2012), 394–402.
24. Calimet, N., Simoes, M., Changeux, J.P., Karplus, M., Taly, A., Cecchini, M., A gating mechanism of pentameric ligand-gated ion channels. Proc. Natl. Acad. Sci. USA 110 (2013), E3987–E3996.
25. Canals, M., Sexton, P.M., Christopoulos, A., Allostery in GPCRs: ‘MWC’ revisited. Trends Biochem. Sci. 36 (2011), 663–672.
26. Cao, E., Liao, M., Cheng, Y., Julius, D., TRPV1 structures in distinct conformations reveal activation mechanisms. Nature 504 (2013), 113–118.
27. Catterall, W.A., Ion channel voltage sensors: structure, function, and pathophysiology. Neuron 67 (2010), 915–928.
28. Catterall, W.A., Swanson, T.M., Structural Basis for Pharmacology of Voltage-Gated Sodium and Calcium Channels. Mol. Pharmacol. 88 (2015), 141–150.
29. Catterall, W.A., Goldin, A.L., Waxman, S.G., International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57 (2005), 397–409.
30. Catterall, W.A., Perez-Reyes, E., Snutch, T.P., Striessnig, J., International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacol. Rev. 57 (2005), 411–425.
31. Catterall, W.A., Cestèle, S., Yarov-Yarovoy, V., Yu, F.H., Konoki, K., Scheuer, T., Voltage-gated ion channels and gating modifier toxins. Toxicon 49 (2007), 124–141.
32. Cecchini, M., Changeux, J.P., The nicotinic acetylcholine receptor and its prokaryotic homologues: Structure, conformational transitions & allosteric modulation. Neuropharmacology 96:Pt B (2015), 137–149.
33. Cestèle, S., Catterall, W.A., Molecular mechanisms of neurotoxin action on voltage-gated sodium channels. Biochimie 82 (2000), 883–892.
34. Chandra, V., Huang, P., Hamuro, Y., Raghuram, S., Wang, Y., Burris, T.P., Rastinejad, F., Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA. Nature 456 (2008), 350–356.
35. Chandra, V., Huang, P., Potluri, N., Wu, D., Kim, Y., Rastinejad, F., Multidomain integration in the structure of the HNF-4α nuclear receptor complex. Nature 495 (2013), 394–398.
36. Changeux, J.P., The feedback control mechanisms of biosynthetic L-threonine deaminase by L-isoleucine. Cold Spring Harb. Symp. Quant. Biol. 26 (1961), 313–318.
37. Changeux, J.P., Allosteric Interactions Interpreted in Terms of Quaternary Structure. Brookhaven Symp. Biol. 17 (1964), 232–249.
38. Changeux, J.-P., On the Allosteric Properties of Biosynthetic L-Threonine Deaminase. Vi. General Discussion. Bull. Soc. Chim. Biol. 47 (1965), 281–300.
39. Changeux, J.-P., Functional architecture and dynamics of the nicotinic acetylcholine receptor: an allosteric ligand-gated ion channel. Llinas, R., Purves, D., Bloom, F., (eds.) Fidia Resarch Foundation Neuroscience Award Lectures, 1990, Raven Press, 21–168.
40. Changeux, J.P., Allostery and the Monod-Wyman-Changeux model after 50 years. Annu. Rev. Biophys. 41 (2012), 103–133.
41. Changeux, J.P., 50 years of allosteric interactions: the twists and turns of the models. Nat. Rev. Mol. Cell Biol. 14 (2013), 819–829.
42. Changeux, J.P., The concept of allosteric modulation: an overview. Drug Discov. Today. Technol. 10 (2013), e223–e228.
43. Changeux, J.P., Edelstein, S.J., Allosteric mechanisms of signal transduction. Science 308 (2005), 1424–1428.
44. Changeux, J.P., Edelstein, S., Conformational selection or induced fit? 50 years of debate resolved. F1000 Biol. Rep., 2011, 10.3410/B3-19 Published online September 1, 2011.
45. Changeux, J.P., Thiéry, J., Tung, Y., Kittel, C., On the cooperativity of biological membranes. Proc. Natl. Acad. Sci. USA 57 (1967), 335–341.
46. Chatzidaki, A., Millar, N.S., Allosteric modulation of nicotinic acetylcholine receptors. Biochem. Pharmacol. 97 (2015), 408–417.
47. Cho, H.S., Mason, K., Ramyar, K.X., Stanley, A.M., Gabelli, S.B., Denney, D.W. Jr., Leahy, D.J., Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421 (2003), 756–760.
48. Christopoulos, A., Allosteric binding sites on cell-surface receptors: novel targets for drug discovery. Nat. Rev. Drug Discov. 1 (2002), 198–210.
49. Christopoulos, A., Advances in G protein-coupled receptor allostery: from function to structure. Mol. Pharmacol. 86 (2014), 463–478.
50. Christopoulos, A., Kenakin, T., G protein-coupled receptor allosterism and complexing. Pharmacol. Rev. 54 (2002), 323–374.
51. Christopoulos, A., Changeux, J.P., Catterall, W.A., Fabbro, D., Burris, T.P., Cidlowski, J.A., Olsen, R.W., Peters, J.A., Neubig, R.R., Pin, J.P., et al. International Union of Basic and Clinical Pharmacology. XC. multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands. Pharmacol. Rev. 66 (2014), 918–947.
52. Conn, P.J., Christopoulos, A., Lindsley, C.W., Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat. Rev. Drug Discov. 8 (2009), 41–54.
53. Corbin, J.A., Bhaskar, V., Goldfine, I.D., Bedinger, D.H., Lau, A., Michelson, K., Gross, L.M., Maddux, B.A., Kuan, H.F., Tran, C., et al. Improved glucose metabolism in vitro and in vivo by an allosteric monoclonal antibody that increases insulin receptor binding affinity. PLoS ONE, 9, 2014, e88684.
54. Corringer, P.J., Poitevin, F., Prevost, M.S., Sauguet, L., Delarue, M., Changeux, J.P., Structure and pharmacology of pentameric receptor channels: from bacteria to brain. Structure 20 (2012), 941–956.
55. Cui, Q., Karplus, M., Allostery and cooperativity revisited. Protein Sci. 17 (2008), 1295–1307.
56. De Smet, F., Christopoulos, A., Carmeliet, P., Allosteric targeting of receptor tyrosine kinases. Nat. Biotechnol. 32 (2014), 1113–1120.
57. Deupi, X., Standfuss, J., Schertler, G., Conserved activation pathways in G-protein-coupled receptors. Biochem. Soc. Trans. 40 (2012), 383–388.
58. DeVree, B.T., Mahoney, J.P., Vélez-Ruiz, G.A., Rasmussen, S.G.F., Kuszak, A.J., Edwald, E., Fung, J.-J., Manglik, A., Masureel, M., Du, Y., et al. Allosteric coupling from G protein to the agonist-binding pocket in GPCRs. Nature 535 (2016), 182–186.
59. Didenko, T., Liu, J.J., Horst, R., Stevens, R.C., Wüthrich, K., Fluorine-19 NMR of integral membrane proteins illustrated with studies of GPCRs. Curr. Opin. Struct. Biol. 23 (2013), 740–747.
60. Du, J., Lü, W., Wu, S., Cheng, Y., Gouaux, E., Glycine receptor mechanism elucidated by electron cryo-microscopy. Nature 526 (2015), 224–229.
61. Dunker, A.K., Garner, E., Guilliot, S., Romero, P., Albrecht, K., Hart, J., Obradovic, Z., Kissinger, C., Villafranca, J.E., Protein disorder and the evolution of molecular recognition: theory, predictions and observations. Pac. Symp. Biocomput., 1998, 473–484.
62. Dunker, A.K., Silman, I., Uversky, V.N., Sussman, J.L., Function and structure of inherently disordered proteins. Curr. Opin. Struct. Biol. 18 (2008), 756–764.
63. Dürr, K.L., Chen, L., Stein, R.A., De Zorzi, R., Folea, I.M., Walz, T., Mchaourab, H.S., Gouaux, E., Structure and dynamics of AMPA receptor GluA2 in resting, pre-open, and desensitized states. Cell 158 (2014), 778–792.
64. Edelstein, S.J., Changeux, J.P., Relationships between structural dynamics and functional kinetics in oligomeric membrane receptors. Biophys. J. 98 (2010), 2045–2052.
65. Eginton, C., Cressman, W.J., Bachas, S., Wade, H., Beckett, D., Allosteric coupling via distant disorder-to-order transitions. J. Mol. Biol. 427 (2015), 1695–1704.
66. Ellis, I.R., Schor, A.M., Schor, S.L., EGF AND TGF-alpha motogenic activities are mediated by the EGF receptor via distinct matrix-dependent mechanisms. Exp. Cell Res. 313 (2007), 732–741.
67. Endres, N.F., Das, R., Smith, A.W., Arkhipov, A., Kovacs, E., Huang, Y., Pelton, J.G., Shan, Y., Shaw, D.E., Wemmer, D.E., et al. Conformational coupling across the plasma membrane in activation of the EGF receptor. Cell 152 (2013), 543–556.
68. Endres, N.F., Barros, T., Cantor, A.J., Kuriyan, J., Emerging concepts in the regulation of the EGF receptor and other receptor tyrosine kinases. Trends Biochem. Sci. 39 (2014), 437–446.
69. Estébanez-Perpiñá, E., Arnold, L.A., Jouravel, N., Togashi, M., Blethrow, J., Mar, E., Nguyen, P., Phillips, K.J., Baxter, J.D., Webb, P., et al. Structural insight into the mode of action of a direct inhibitor of coregulator binding to the thyroid hormone receptor. Mol. Endocrinol. 21 (2007), 2919–2928.
70. Estébanez-Perpiñá, E., Arnold, L.A., Nguyen, P., Rodrigues, E.D., Mar, E., Bateman, R., Pallai, P., Shokat, K.M., Baxter, J.D., Guy, R.K., et al. A surface on the androgen receptor that allosterically regulates coactivator binding. Proc. Natl. Acad. Sci. USA 104 (2007), 16074–16079.
71. Fabbro, D., 25 years of small molecular weight kinase inhibitors: potentials and limitations. Mol. Pharmacol. 87 (2015), 766–775.
72. Fischer, E.H., Protein phosphorylation and cellular regulation. Nobel lecture, 1992 http://www.nobelprize.org/nobel_prizes/medicine/laureates/1992/fischer-lecture.html.
73. Flock, T., Ravarani, C.N., Sun, D., Venkatakrishnan, A.J., Kayikci, M., Tate, C.G., Veprintsev, D.B., Babu, M.M., Universal allosteric mechanism for Gα activation by GPCRs. Nature 524 (2015), 173–179.
74. Fotiadis, D., Liang, Y., Filipek, S., Saperstein, D.A., Engel, A., Palczewski, K., Atomic-force microscopy: Rhodopsin dimers in native disc membranes. Nature 421 (2003), 127–128.
75. Fourati, Z., Sauguet, L., Delarue, M., Genuine open form of the pentameric ligand-gated ion channel GLIC. Acta Crystallogr. D Biol. Crystallogr. 71 (2015), 454–460.
76. Franklin, M.C., Carey, K.D., Vajdos, F.F., Leahy, D.J., de Vos, A.M., Sliwkowski, M.X., Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 5 (2004), 317–328.
77. Galzi, J.L., Changeux, J.P., Neurotransmitter-gated ion channels as unconventional allosteric proteins. Curr. Opin. Struct. Biol. 4 (1994), 554–565.
78. Galzi, J.-L., Edelstein, S.J., Changeux, J., The multiple phenotypes of allosteric receptor mutants. Proc. Natl. Acad. Sci. USA 93 (1996), 1853–1858.
79. Galzi, J.L., Bertrand, S., Corringer, P.J., Changeux, J.P., Bertrand, D., Identification of calcium binding sites that regulate potentiation of a neuronal nicotinic acetylcholine receptor. EMBO J. 15 (1996), 5824–5832.
80. Gay, N.J., Symmons, M.F., Gangloff, M., Bryant, C.E., Assembly and localization of Toll-like receptor signalling complexes. Nat. Rev. Immunol. 14 (2014), 546–558.
81. Gentry, P.R., Sexton, P.M., Christopoulos, A., Novel Allosteric Modulators of G Protein-coupled Receptors. J. Biol. Chem. 290 (2015), 19478–19488.
82. Grosman, C., Zhou, M., Auerbach, A., Mapping the conformational wave of acetylcholine receptor channel gating. Nature 403 (2000), 773–776.
83. Hall, J.M., McDonnell, D.P., Korach, K.S., Allosteric regulation of estrogen receptor structure, function, and coactivator recruitment by different estrogen response elements. Mol. Endocrinol. 16 (2002), 469–486.
84. Hassaine, G., Deluz, C., Grasso, L., Wyss, R., Tol, M.B., Hovius, R., Graff, A., Stahlberg, H., Tomizaki, T., Desmyter, A., et al. X-ray structure of the mouse serotonin 5-HT3 receptor. Nature 512 (2014), 276–281.
85. Hattori, M., Gouaux, E., Molecular mechanism of ATP binding and ion channel activation in P2X receptors. Nature 485 (2012), 207–212.
86. Hénin, J., Salari, R., Murlidaran, S., Brannigan, G., A predicted binding site for cholesterol on the GABAA receptor. Biophys. J. 106 (2014), 1938–1949.
87. Herbert, C., Schieborr, U., Saxena, K., Juraszek, J., De Smet, F., Alcouffe, C., Bianciotto, M., Saladino, G., Sibrac, D., Kudlinzki, D., et al. Molecular mechanism of SSR128129E, an extracellularly acting, small-molecule, allosteric inhibitor of FGF receptor signaling. Cancer Cell 23 (2013), 489–501.
88. Herz, J.M., Johnson, D.A., Taylor, P., Distance between the agonist and noncompetitive inhibitor sites on the nicotinic acetylcholine receptor. J. Biol. Chem. 264 (1989), 12439–12448.
89. Hibbs, R.E., Gouaux, E., Principles of activation and permeation in an anion-selective Cys-loop receptor. Nature 474 (2011), 54–60.
90. Hicklin, D.J., Witte, L., Zhu, Z., Liao, F., Wu, Y., Li, Y., Bohlen, P., Monoclonal antibody strategies to block angiogenesis. Drug Discov. Today 6 (2001), 517–528.
91. Hilf, R.J., Dutzler, R., X-ray structure of a prokaryotic pentameric ligand-gated ion channel. Nature 452 (2008), 375–379.
92. Hilf, R.J., Dutzler, R., Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel. Nature 457 (2009), 115–118.
93. Hill, K.K., Roemer, S.C., Churchill, M.E., Edwards, D.P., Structural and functional analysis of domains of the progesterone receptor. Mol. Cell. Endocrinol. 348 (2012), 418–429.
94. Hilser, V.J., Thompson, E.B., Intrinsic disorder as a mechanism to optimize allosteric coupling in proteins. Proc. Natl. Acad. Sci. USA 104 (2007), 8311–8315.
95. Horst, R., Stanczak, P., Stevens, R.C., Wüthrich, K., β2-Adrenergic receptor solutions for structural biology analyzed with microscale NMR diffusion measurements. Angew. Chem. Int. Ed. Engl. 52 (2013), 331–335.
96. Huang, Z., Zhu, L., Cao, Y., Wu, G., Liu, X., Chen, Y., Wang, Q., Shi, T., Zhao, Y., Wang, Y., et al. ASD: a comprehensive database of allosteric proteins and modulators. Nucleic Acids Res. 39 (2011), D663–D669.
97. Hubbard, S.R., Structural analysis of receptor tyrosine kinases. Prog. Biophys. Mol. Biol. 71 (1999), 343–358.
98. Hubbard, S.R., Juxtamembrane autoinhibition in receptor tyrosine kinases. Nat. Rev. Mol. Cell Biol. 5 (2004), 464–471.
99. Hübner, C.A., Jentsch, T.J., Ion channel diseases. Hum. Mol. Genet. 11 (2002), 2435–2445.
100. Hughes, T.S., Giri, P.K., de Vera, I.M., Marciano, D.P., Kuruvilla, D.S., Shin, Y., Blayo, A.L., Kamenecka, T.M., Burris, T.P., Griffin, P.R., Kojetin, D.J., An alternate binding site for PPARγ ligands. Nat. Commun., 5, 2014, 3571.
101. Huse, M., Kuriyan, J., The conformational plasticity of protein kinases. Cell 109 (2002), 275–282.
102. Hynes, R.O., Integrins: bidirectional, allosteric signaling machines. Cell 110 (2002), 673–687.
103. Jang, S.W., Okada, M., Sayeed, I., Xiao, G., Stein, D., Jin, P., Ye, K., Gambogic amide, a selective agonist for TrkA receptor that possesses robust neurotrophic activity, prevents neuronal cell death. Proc. Natl. Acad. Sci. USA 104 (2007), 16329–16334.
104. Jasti, J., Furukawa, H., Gonzales, E.B., Gouaux, E., Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH. Nature 449 (2007), 316–323.
105. Jordan, V.C., Chemoprevention of breast cancer with selective oestrogen-receptor modulators. Nat. Rev. Cancer 7 (2007), 46–53.
106. Kang, Y., Zhou, X.E., Gao, X., He, Y., Liu, W., Ishchenko, A., Barty, A., White, T.A., Yefanov, O., Han, G.W., et al. Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser. Nature 523 (2015), 561–567.
107. Karakas, E., Furukawa, H., Crystal structure of a heterotetrameric NMDA receptor ion channel. Science 344 (2014), 992–997.
108. Karakas, E., Simorowski, N., Furukawa, H., Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors. Nature 475 (2011), 249–253.
109. Karlin, A., On the application of “a plausible model” of allosteric proteins to the receptor for acetylcholine. J. Theor. Biol. 16 (1967), 306–320.
110. Katz, B., Thesleff, S., A study of the desensitization produced by acetylcholine at the motor end-plate. J. Physiol. 138 (1957), 63–80.
111. Kawate, T., Michel, J.C., Birdsong, W.T., Gouaux, E., Crystal structure of the ATP-gated P2X(4) ion channel in the closed state. Nature 460 (2009), 592–598.
112. Kenakin, T., Agonist-receptor efficacy. II. Agonist trafficking of receptor signals. Trends Pharmacol. Sci. 16 (1995), 232–238.
113. Kenakin, T., Christopoulos, A., Signalling bias in new drug discovery: detection, quantification and therapeutic impact. Nat. Rev. Drug Discov. 12 (2013), 205–216.
114. Keov, P., Sexton, P.M., Christopoulos, A., Allosteric modulation of G protein-coupled receptors: a pharmacological perspective. Neuropharmacology 60 (2011), 24–35.
115. Kniazeff, J., Prézeau, L., Rondard, P., Pin, J.P., Goudet, C., Dimers and beyond: The functional puzzles of class C GPCRs. Pharmacol. Ther. 130 (2011), 9–25.
116. Kojetin, D.J., Burris, T.P., Jensen, E.V., Khan, S.A., Implications of the binding of tamoxifen to the coactivator recognition site of the estrogen receptor. Endocr. Relat. Cancer 15 (2008), 851–870.
117. Koshland, D.E. Jr., Némethy, G., Filmer, D., Comparison of experimental binding data and theoretical models in proteins containing subunits. Biochemistry 5 (1966), 365–385.
118. Krause, R.M., Buisson, B., Bertrand, S., Corringer, P.J., Galzi, J.L., Changeux, J.P., Bertrand, D., Ivermectin: a positive allosteric effector of the alpha7 neuronal nicotinic acetylcholine receptor. Mol. Pharmacol. 53 (1998), 283–294.
119. Kruse, A.C., Ring, A.M., Manglik, A., Hu, J., Hu, K., Eitel, K., Hübner, H., Pardon, E., Valant, C., Sexton, P.M., et al. Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature 504 (2013), 101–106.
120. Kruse, A.C., Kobilka, B.K., Gautam, D., Sexton, P.M., Christopoulos, A., Wess, J., Muscarinic acetylcholine receptors: novel opportunities for drug development. Nat. Rev. Drug Discov. 13 (2014), 549–560.
121. Kuszak, A.J., Pitchiaya, S., Anand, J.P., Mosberg, H.I., Walter, N.G., Sunahara, R.K., Purification and functional reconstitution of monomeric mu-opioid receptors: allosteric modulation of agonist binding by Gi2. J. Biol. Chem. 284 (2009), 26732–26741.
122. Kuzmenkin, A., Bezanilla, F., Correa, A.M., Gating of the bacterial sodium channel, NaChBac: voltage-dependent charge movement and gating currents. J. Gen. Physiol. 124 (2004), 349–356.
123. Lamichhane, R., Liu, J.J., Pljevaljcic, G., White, K.L., van der Schans, E., Katritch, V., Stevens, R.C., Wüthrich, K., Millar, D.P., Single-molecule view of basal activity and activation mechanisms of the G protein-coupled receptor β2AR. Proc. Natl. Acad. Sci. USA 112 (2015), 14254–14259.
124. Lape, R., Colquhoun, D., Sivilotti, L.G., On the nature of partial agonism in the nicotinic receptor superfamily. Nature 454 (2008), 722–727.
125. Le Novère, N., Grutter, T., Changeux, J.P., Models of the extracellular domain of the nicotinic receptors and of agonist- and Ca2+-binding sites. Proc. Natl. Acad. Sci. USA 99 (2002), 3210–3215.
126. Leach, K., Conigrave, A.D., Sexton, P.M., Christopoulos, A., Towards tissue-specific pharmacology: insights from the calcium-sensing receptor as a paradigm for GPCR (patho)physiological bias. Trends Pharmacol. Sci. 36 (2015), 215–225.
127. Lee, C.H., Lü, W., Michel, J.C., Goehring, A., Du, J., Song, X., Gouaux, E., NMDA receptor structures reveal subunit arrangement and pore architecture. Nature 511 (2014), 191–197.
128. Lee, J.H., Park, C.K., Chen, G., Han, Q., Xie, R.G., Liu, T., Ji, R.R., Lee, S.Y., A monoclonal antibody that targets a NaV1.7 channel voltage sensor for pain and itch relief. Cell 157 (2014), 1393–1404.
129. Leff, P., Scaramellini, C., Law, C., McKechnie, K., A three-state receptor model of agonist action. Trends Pharmacol. Sci. 18 (1997), 355–362.
130. Lemmon, M.A., Schlessinger, J., Cell signaling by receptor tyrosine kinases. Cell 141 (2010), 1117–1134.
131. Lewis, M., Response: DNA Looping and Lac Repressor—CAP Interaction. Science 274 (1996), 1931–1932.
132. Lewis, M., The lac repressor. C. R. Biol. 328 (2005), 521–548.
133. Li, Y., Lambert, M.H., Xu, H.E., Activation of nuclear receptors: a perspective from structural genomics. Structure 11 (2003), 741–746.
134. Li, G.D., Chiara, D.C., Sawyer, G.W., Husain, S.S., Olsen, R.W., Cohen, J.B., Identification of a GABAA receptor anesthetic binding site at subunit interfaces by photolabeling with an etomidate analog. J. Neurosci. 26 (2006), 11599–11605.
135. Liao, M., Cao, E., Julius, D., Cheng, Y., Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature 504 (2013), 107–112.
136. Liu, J.J., Horst, R., Katritch, V., Stevens, R.C., Wüthrich, K., Biased signaling pathways in β2-adrenergic receptor characterized by 19F-NMR. Science 335 (2012), 1106–1110.
137. Mackinnon, J.A., Gallastegui, N., Osguthorpe, D.J., Hagler, A.T., Estébanez-Perpiñá, E., Allosteric mechanisms of nuclear receptors: insights from computational simulations. Mol. Cell. Endocrinol. 393 (2014), 75–82.
138. Maguire, M.E., Van Arsdale, P.M., Gilman, A.G., An agonist-specific effect of guanine nucleotides on binding to the beta adrenergic receptor. Mol. Pharmacol. 12 (1976), 335–339.
139. Manglik, A., Kobilka, B., The role of protein dynamics in GPCR function: insights from the β2AR and rhodopsin. Curr. Opin. Cell Biol. 27 (2014), 136–143.
140. Manglik, A., Kruse, A.C., Kobilka, T.S., Thian, F.S., Mathiesen, J.M., Sunahara, R.K., Pardo, L., Weis, W.I., Kobilka, B.K., Granier, S., Crystal structure of the μ-opioid receptor bound to a morphinan antagonist. Nature 485 (2012), 321–326.
141. Meijsing, S.H., Pufall, M.A., So, A.Y., Bates, D.L., Chen, L., Yamamoto, K.R., DNA binding site sequence directs glucocorticoid receptor structure and activity. Science 324 (2009), 407–410.
142. Meyerson, J.R., Kumar, J., Chittori, S., Rao, P., Pierson, J., Bartesaghi, A., Mayer, M.L., Subramaniam, S., Structural mechanism of glutamate receptor activation and desensitization. Nature 514 (2014), 328–334.
143. Miller, P.S., Aricescu, A.R., Crystal structure of a human GABAA receptor. Nature 512 (2014), 270–275.
144. Minezaki, Y., Homma, K., Nishikawa, K., Intrinsically disordered regions of human plasma membrane proteins preferentially occur in the cytoplasmic segment. J. Mol. Biol. 368 (2007), 902–913.
145. Monod, J., Jacob, F., Teleonomic mechanisms in cellular metabolism, growth, and differentiation. Cold Spring Harb. Symp. Quant. Biol. 26 (1961), 389–401.
146. Monod, J., Wyman, J., Changeux, J.P., On the Nature of Allosteric Transitions: A Plausible Model. J. Mol. Biol. 12 (1965), 88–118.
147. Moore, T.W., Mayne, C.G., Katzenellenbogen, J.A., Minireview: Not picking pockets: nuclear receptor alternate-site modulators (NRAMs). Mol. Endocrinol. 24 (2010), 683–695.
148. Motlagh, H.N., Wrabl, J.O., Li, J., Hilser, V.J., The ensemble nature of allostery. Nature 508 (2014), 331–339.
149. Mukund, S., Shang, Y., Clarke, H.J., Madjidi, A., Corn, J.E., Kates, L., Kolumam, G., Chiang, V., Luis, E., Murray, J., et al. Inhibitory mechanism of an allosteric antibody targeting the glucagon receptor. J. Biol. Chem. 288 (2013), 36168–36178.
150. Mulle, C., Léna, C., Changeux, J.P., Potentiation of nicotinic receptor response by external calcium in rat central neurons. Neuron 8 (1992), 937–945.
151. Nilius, B., Talavera, K., Owsianik, G., Prenen, J., Droogmans, G., Voets, T., Gating of TRP channels: a voltage connection?. J. Physiol. 567 (2005), 35–44.
152. Nury, H., Poitevin, F., Van Renterghem, C., Changeux, J.P., Corringer, P.J., Delarue, M., Baaden, M., One-microsecond molecular dynamics simulation of channel gating in a nicotinic receptor homologue. Proc. Natl. Acad. Sci. USA 107 (2010), 6275–6280.
153. Nury, H., Van Renterghem, C., Weng, Y., Tran, A., Baaden, M., Dufresne, V., Changeux, J.P., Sonner, J.M., Delarue, M., Corringer, P.J., X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel. Nature 469 (2011), 428–431.
154. Nussinov, R., Tsai, C.J., Free energy diagrams for protein function. Chem. Biol. 21 (2014), 311–318.
155. Olsen, R.W., Analysis of γ-aminobutyric acid (GABA) type A receptor subtypes using isosteric and allosteric ligands. Neurochem. Res. 39 (2014), 1924–1941.
156. Orlov, I., Rochel, N., Moras, D., Klaholz, B.P., Structure of the full human RXR/VDR nuclear receptor heterodimer complex with its DR3 target DNA. EMBO J. 31 (2012), 291–300.
157. Partin, K.M., AMPA receptor potentiators: from drug design to cognitive enhancement. Curr. Opin. Pharmacol. 20 (2015), 46–53.
158. Payandeh, J., Scheuer, T., Zheng, N., Catterall, W.A., The crystal structure of a voltage-gated sodium channel. Nature 475 (2011), 353–358.
159. Perez, D.M., From plants to man: the GPCR “tree of life”. Mol. Pharmacol. 67 (2005), 1383–1384.
160. Prevost, M.S., Sauguet, L., Nury, H., Van Renterghem, C., Huon, C., Poitevin, F., Baaden, M., Delarue, M., Corringer, P.J., A locally closed conformation of a bacterial pentameric proton-gated ion channel. Nat. Struct. Mol. Biol. 19 (2012), 642–649.
161. Prevost, M.S., Moraga-Cid, G., Van Renterghem, C., Edelstein, S.J., Changeux, J.P., Corringer, P.J., Intermediate closed state for glycine receptor function revealed by cysteine cross-linking. Proc. Natl. Acad. Sci. USA 110 (2013), 17113–17118.
162. Purohit, P., Mitra, A., Auerbach, A., A stepwise mechanism for acetylcholine receptor channel gating. Nature 446 (2007), 930–933.
163. Rasmussen, S.G., DeVree, B.T., Zou, Y., Kruse, A.C., Chung, K.Y., Kobilka, T.S., Thian, F.S., Chae, P.S., Pardon, E., Calinski, D., et al. Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature 477 (2011), 549–555.
164. Regalado, M.P., Villarroel, A., Lerma, J., Intersubunit cooperativity in the NMDA receptor. Neuron 32 (2001), 1085–1096.
165. Renaud, J.P., Rochel, N., Ruff, M., Vivat, V., Chambon, P., Gronemeyer, H., Moras, D., Crystal structure of the RAR-gamma ligand-binding domain bound to all-trans retinoic acid. Nature 378 (1995), 681–689.
166. Rizk, S.S., Kouadio, J.L., Szymborska, A., Duguid, E.M., Mukherjee, S., Zheng, J., Clevenger, C.V., Kossiakoff, A.A., Engineering synthetic antibody binders for allosteric inhibition of prolactin receptor signaling. Cell Commun. Signal., 13, 2015, 1.
167. Rondard, P., Pin, J.P., Dynamics and modulation of metabotropic glutamate receptors. Curr. Opin. Pharmacol. 20 (2015), 95–101.
168. Rowlinson, S.W., Yoshizato, H., Barclay, J.L., Brooks, A.J., Behncken, S.N., Kerr, L.M., Millard, K., Palethorpe, K., Nielsen, K., Clyde-Smith, J., et al. An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway. Nat. Cell Biol. 10 (2008), 740–747.
169. Rubin, M.M., Changeux, J.-P., On the nature of allosteric transitions: implications of non-exclusive ligand binding. J. Mol. Biol. 21 (1966), 265–274.
170. Sauguet, L., Howard, R.J., Malherbe, L., Lee, U.S., Corringer, P.J., Harris, R.A., Delarue, M., Structural basis for potentiation by alcohols and anaesthetics in a ligand-gated ion channel. Nat. Commun., 4, 2013, 1697.
171. Sauguet, L., Shahsavar, A., Poitevin, F., Huon, C., Menny, A., Nemecz, À., Haouz, A., Changeux, J.P., Corringer, P.J., Delarue, M., Crystal structures of a pentameric ligand-gated ion channel provide a mechanism for activation. Proc. Natl. Acad. Sci. USA 111 (2014), 966–971.
172. Sawyer, G.W., Chiara, D.C., Olsen, R.W., Cohen, J.B., Identification of the bovine gamma-aminobutyric acid type A receptor alpha subunit residues photolabeled by the imidazobenzodiazepine [3H]Ro15-4513. J. Biol. Chem. 277 (2002), 50036–50045.
173. Schlessinger, J., Cell signaling by receptor tyrosine kinases. Cell 103 (2000), 211–225.
174. Schürpf, T., Springer, T.A., Regulation of integrin affinity on cell surfaces. EMBO J. 30 (2011), 4712–4727.
175. Schwarz, M., Meade, G., Stoll, P., Ylanne, J., Bassler, N., Chen, Y.C., Hagemeyer, C.E., Ahrens, I., Moran, N., Kenny, D., et al. Conformation-specific blockade of the integrin GPIIb/IIIa: a novel antiplatelet strategy that selectively targets activated platelets. Circ. Res. 99 (2006), 25–33.
176. Shan, Y., Eastwood, M.P., Zhang, X., Kim, E.T., Arkhipov, A., Dror, R.O., Jumper, J., Kuriyan, J., Shaw, D.E., Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization. Cell 149 (2012), 860–870.
177. Sharon, M., Horovitz, A., Probing allosteric mechanisms using native mass spectrometry. Curr. Opin. Struct. Biol. 34 (2015), 7–16.
178. Shukla, A.K., Manglik, A., Kruse, A.C., Xiao, K., Reis, R.I., Tseng, W.C., Staus, D.P., Hilger, D., Uysal, S., Huang, L.Y., et al. Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide. Nature 497 (2013), 137–141.
179. Shulman, A.I., Larson, C., Mangelsdorf, D.J., Ranganathan, R., Structural determinants of allosteric ligand activation in RXR heterodimers. Cell 116 (2004), 417–429.
180. Simon, A.J., Vallée-Bélisle, A., Ricci, F., Plaxco, K.W., Intrinsic disorder as a generalizable strategy for the rational design of highly responsive, allosterically cooperative receptors. Proc. Natl. Acad. Sci. USA 111 (2014), 15048–15053.
181. Simons, S.S. Jr., Edwards, D.P., Kumar, R., Minireview: dynamic structures of nuclear hormone receptors: new promises and challenges. Mol. Endocrinol. 28 (2014), 173–182.
182. Smith, N.J., Milligan, G., Allostery at G protein-coupled receptor homo- and heteromers: uncharted pharmacological landscapes. Pharmacol. Rev. 62 (2010), 701–725.
183. Smith, G.B., Olsen, R.W., Deduction of amino acid residues in the GABA(A) receptor alpha subunits photoaffinity labeled with the benzodiazepine flunitrazepam. Neuropharmacology 39 (2000), 55–64.
184. Sobolevsky, A.I., Rosconi, M.P., Gouaux, E., X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature 462 (2009), 745–756.
185. Spedding, M., Activators and inactivators of Ca++ channels: new perspectives. J. Pharmacol. 16 (1985), 319–343.
186. Spedding, M., Competitive interactions between Bay K 8644 and nifedipine in K+ depolarized smooth muscle: a passive role for Ca2+?. Naunyn Schmiedebergs Arch. Pharmacol. 328 (1985), 464–466.
187. Spedding, M., Berg, C., Interactions between a “calcium channel agonist”, Bay K 8644, and calcium antagonists differentiate calcium antagonist subgroups in K+-depolarized smooth muscle. Naunyn Schmiedebergs Arch. Pharmacol. 328 (1984), 69–75.
188. Steinlein, O.K., Ion channel mutations in neuronal diseases: a genetics perspective. Chem. Rev. 112 (2012), 6334–6352.
189. Striessnig, J., Pharmacology, structure and function of cardiac L-type Ca(2+) channels. Cell. Physiol. Biochem. 9 (1999), 242–269.
190. Suh, J.M., Jonker, J.W., Ahmadian, M., Goetz, R., Lackey, D., Osborn, O., Huang, Z., Liu, W., Yoshihara, E., van Dijk, T.H., et al. Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature 513 (2014), 436–439.
191. Taly, A., Delarue, M., Grutter, T., Nilges, M., Le Novère, N., Corringer, P.J., Changeux, J.P., Normal mode analysis suggests a quaternary twist model for the nicotinic receptor gating mechanism. Biophys. J. 88 (2005), 3954–3965.
192. Taly, A., Corringer, P.J., Grutter, T., Prado de Carvalho, L., Karplus, M., Changeux, J.P., Implications of the quaternary twist allosteric model for the physiology and pathology of nicotinic acetylcholine receptors. Proc. Natl. Acad. Sci. USA 103 (2006), 16965–16970.
193. Taly, A., Corringer, P.J., Guedin, D., Lestage, P., Changeux, J.P., Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system. Nat. Rev. Drug Discov. 8 (2009), 733–750.
194. Tao, Y.X., Constitutive activation of G protein-coupled receptors and diseases: insights into mechanisms of activation and therapeutics. Pharmacol. Ther. 120 (2008), 129–148.
195. Tenbaum, S., Baniahmad, A., Nuclear receptors: structure, function and involvement in disease. Int. J. Biochem. Cell Biol. 29 (1997), 1325–1341.
196. Traynelis, S.F., Wollmuth, L.P., McBain, C.J., Menniti, F.S., Vance, K.M., Ogden, K.K., Hansen, K.B., Yuan, H., Myers, S.J., Dingledine, R., Glutamate receptor ion channels: structure, regulation, and function. Pharmacol. Rev. 62 (2010), 405–496.
197. Tsai, C.J., Nussinov, R., A unified view of “how allostery works”. PLoS Comput. Biol., 10, 2014, e1003394.
198. Tsigelny, I.F., Mukthavaram, R., Kouznetsova, V.L., Chao, Y., Babic, I., Nurmemmedov, E., Pastorino, S., Jiang, P., Calligaris, D., Agar, N., et al. Multiple spatially related pharmacophores define small molecule inhibitors of OLIG2 in glioblastoma. Oncotarget, 2015, 10.18632/oncotarget.5633 Published online October 30, 2015.
199. Ullrich, A., Schlessinger, J., Signal transduction by receptors with tyrosine kinase activity. Cell 61 (1990), 203–212.
200. van der Westhuizen, E.T., Valant, C., Sexton, P.M., Christopoulos, A., Endogenous allosteric modulators of G protein-coupled receptors. J. Pharmacol. Exp. Ther. 353 (2015), 246–260.
201. Vassart, G., Costagliola, S., G protein-coupled receptors: mutations and endocrine diseases. Nat. Rev. Endocrinol. 7 (2011), 362–372.
202. Venkatakrishnan, A.J., Deupi, X., Lebon, G., Tate, C.G., Schertler, G.F., Babu, M.M., Molecular signatures of G-protein-coupled receptors. Nature 494 (2013), 185–194.
203. Vernino, S., Amador, M., Luetje, C.W., Patrick, J., Dani, J.A., Calcium modulation and high calcium permeability of neuronal nicotinic acetylcholine receptors. Neuron 8 (1992), 127–134.
204. Violin, J.D., Lefkowitz, R.J., Beta-arrestin-biased ligands at seven-transmembrane receptors. Trends Pharmacol. Sci. 28 (2007), 416–422.
205. Wang, C., Wu, H., Katritch, V., Han, G.W., Huang, X.P., Liu, W., Siu, F.Y., Roth, B.L., Cherezov, V., Stevens, R.C., Structure of the human smoothened receptor bound to an antitumour agent. Nature 497 (2013), 338–343.
206. Weber, G., Ligand binding and internal equilibria in proteins. Biochemistry 11 (1972), 864–878.
207. Whorton, M.R., Bokoch, M.P., Rasmussen, S.G., Huang, B., Zare, R.N., Kobilka, B., Sunahara, R.K., A monomeric G protein-coupled receptor isolated in a high-density lipoprotein particle efficiently activates its G protein. Proc. Natl. Acad. Sci. USA 104 (2007), 7682–7687.
208. Wiesmann, C., Ultsch, M.H., Bass, S.H., de Vos, A.M., Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor. Nature 401 (1999), 184–188.
209. Wootten, D., Christopoulos, A., Sexton, P.M., Emerging paradigms in GPCR allostery: implications for drug discovery. Nat. Rev. Drug Discov. 12 (2013), 630–644.
210. Wright, P.E., Dyson, H.J., Intrinsically disordered proteins in cellular signalling and regulation. Nat. Rev. Mol. Cell Biol. 16 (2015), 18–29.
211. Wu, B., Chien, E.Y., Mol, C.D., Fenalti, G., Liu, W., Katritch, V., Abagyan, R., Brooun, A., Wells, P., Bi, F.C., et al. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 330 (2010), 1066–1071.
212. Wybenga-Groot, L.E., Baskin, B., Ong, S.H., Tong, J., Pawson, T., Sicheri, F., Structural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region. Cell 106 (2001), 745–757.
213. Yelshanskaya, M.V., Li, M., Sobolevsky, A.I., Structure of an agonist-bound ionotropic glutamate receptor. Science 345 (2014), 1070–1074.
214. Yuzawa, S., Opatowsky, Y., Zhang, Z., Mandiyan, V., Lax, I., Schlessinger, J., Structural basis for activation of the receptor tyrosine kinase KIT by stem cell factor. Cell 130 (2007), 323–334.
215. Zagotta, W.N., Hoshi, T., Aldrich, R.W., Shaker potassium channel gating. III: Evaluation of kinetic models for activation. J. Gen. Physiol. 103 (1994), 321–362.
216. Zhao, Y., Yarov-Yarovoy, V., Scheuer, T., Catterall, W.A., A gating hinge in Na+ channels; a molecular switch for electrical signaling. Neuron 41 (2004), 859–865.
217. Zhu, S., Paoletti, P., Allosteric modulators of NMDA receptors: multiple sites and mechanisms. Curr. Opin. Pharmacol. 20 (2015), 14–23.
218. Zimmermann, I., Dutzler, R., Ligand activation of the prokaryotic pentameric ligand-gated ion channel ELIC. PLoS Biol., 9, 2011, e1001101.
219. Zwick, E., Bange, J., Ullrich, A., Receptor tyrosine kinase signalling as a target for cancer intervention strategies. Endocr. Relat. Cancer 8 (2001), 161–173.