Allosteric modulation of a cannabinoid G protein-coupled receptor: Binding site elucidation and relationship to G protein signaling

Journal of Biological Chemistry

Volumn 289, Issue 9, 2014, Pages 5828-5845

  Shore, Derek M ^a   Baillie, Gemma L ^b,c   Hurst, Dow H ^a   Navas III, Frank ^d   Seltzman, Herbert H ^d   Marcu, Jahan P ^e   Abood, Mary E ^e   Ross, Ruth A ^b,c   Reggio, Patricia H ^a  

^a UNIVERSITY OF NORTH CAROLINA AT GREENSBORO   (United States)

^b UNIVERSITY OF ABERDEEN   (United Kingdom)

^c UNIVERSITY OF TORONTO   (Canada)

^d RTI INTERNATIONAL   (United States)

^e TEMPLE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALLOSTERIC MODULATION; ALLOSTERIC MODULATORS; EQUILIBRIUM BINDING; EXTRACELLULAR LOOPS; G PROTEIN COUPLED RECEPTORS; INTERMEDIATE CONFORMATION; LIGAND DISPLACEMENT; RECEPTOR ACTIVATION;

ELECTROSTATIC SEPARATORS;

PROTEINS;

5 CHLORO 3 ETHYL 1H INDOLE 2 CARBOXYLIC ACID [2 (4 PIPERIDIN 1 YL PHENYL)ETHYL] AMIDE; [3H] 3[2 HYDROXYL 4(1,1 DIMETHYLHEPTYL)PHENYL] 4 [3 HYDROXYLPROPYL]CYCLOHEXAN 1 OL; CANNABINOID; CANNABINOID 1; G PROTEIN COUPLED RECEPTOR; MEMBRANE PROTEIN; N (PIPERIDINY 1 YL) 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; TRANSMEMBRANE HELIX 6 PROTEIN; UNCLASSIFIED DRUG;

ARTICLE; BINDING SITE; CONFORMATIONAL TRANSITION; HUMAN; HUMAN CELL; PRIORITY JOURNAL; PROTEIN ACTIVATION; PROTEIN BINDING; PROTEIN CONFORMATION; PROTEIN FUNCTION; PROTEIN MODIFICATION; PROTEIN MUTATION; PROTEIN SYNTHESIS; SIGNAL TRANSDUCTION;

ALLOSTERIC REGULATION; CANNABINOID RECEPTORS; CANNABINOIDS; G PROTEIN-COUPLED RECEPTORS (GPCR); SIGNALING;

ALLOSTERIC REGULATION; BINDING SITES; CANNABINOID RECEPTOR ANTAGONISTS; HEK293 CELLS; HUMANS; INDOLES; MOLECULAR DYNAMICS SIMULATION; PIPERIDINES; PROTEIN BINDING; PYRAZOLES; RECEPTOR, CANNABINOID, CB1; SIGNAL TRANSDUCTION;

EID: 84896891638     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M113.478495     Document Type: Article

References (56)

1. Lagerström, M. C., and Schiöth, H. B. (2008) Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat. Rev. Drug Discov. 7, 339-357
2. Insel, P. A., Tang, C. M., Hahntow, I., and Michel, M. C. (2007) Impact of GPCRs in clinical medicine: monogenic diseases, genetic variants and drug targets. Biochim. Biophys. Acta 1768, 994-1005 (Pubitemid 46452544)
3. McCusker, E. C., Bane, S. E., O'Malley, M. A., and Robinson, A. S. (2007) Heterologous GPCR expression: A bottleneck to obtaining crystal structures. Biotechnol. Prog. 23, 540-547 (Pubitemid 46911176)
4. Wang, C. I., and Lewis, R. J. (2013) Emerging opportunities for allosteric modulation of G-protein coupled receptors. Biochem. Pharmacol. 85, 153-162
5. Kenakin, T. (2005) New concepts in drug discovery: collateral efficacy and permissive antagonism. Nat. Rev. Drug Discov. 4, 919-927
6. Langmead, C. J., and Christopoulos, A. (2006) Allosteric agonists of 7TM receptors: expanding the pharmacological toolbox. Trends Pharmacol. Sci. 27, 475-481 (Pubitemid 44233695)
7. May, L. T., Leach, K., Sexton, P. M., and Christopoulos, A. (2007) Allosteric modulation of G protein-coupled receptors. Annu. Rev. Pharmacol. Toxicol. 47, 1-51 (Pubitemid 46277033)
8. Conn, P. J., Christopoulos, A., and Lindsley, C. W. (2009) Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat. Rev. Drug Discov. 8, 41-54
9. Ahn, K. H., Mahmoud, M. M., and Kendall, D. A. (2012) Allosteric modulator ORG27569 induces CB1 cannabinoid receptor high affinity agonist binding state, receptor internalization, and Gi protein-independent ERK1/2 kinase activation. J. Biol. Chem. 287, 12070-12082
10. Pertwee, R. G. (2009) Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br. J. Pharmacol. 156, 397-411
11. Christopoulou, F. D., and Kiortsis, D. N. (2011) An overview of the metabolic effects of rimonabant in randomized controlled trials: potential for other cannabinoid 1 receptor blockers in obesity. J. Clin. Pharm. Ther. 36, 10-18
12. Ross, R. A. (2007) Allosterism and cannabinoid CB(1) receptors: the shape of things to come. Trends Pharmacol. Sci. 28, 567-572
13. Price, M. R., Baillie, G. L., Thomas, A., Stevenson, L. A., Easson, M., Goodwin, R., McLean, A., McIntosh, L., Goodwin, G., Walker, G., Westwood, P., Marrs, J., Thomson, F., Cowley, P., Christopoulos, A., Pertwee, R. G., and Ross, R. A. (2005) Allosteric modulation of the cannabinoid CB1 receptor. Mol. Pharmacol. 68, 1484-1495 (Pubitemid 41540004)
14. Baillie, G. L., Horswill, J. G., Anavi-Goffer, S., Reggio, P. H., Bolognini, D., Abood, M. E., McAllister, S., Strange, P. G., Stephens, G. J., Pertwee, R. G., and Ross, R. A. (2013) CB(1) receptor allosteric modulators display both agonist and signaling pathway specificity. Mol. Pharmacol. 83, 322-338
15. Ballesteros, J. A., and Weinstein, H. (1995) in Methods in Neuroscience (Sealfon, S. C. ed) pp. 366-428, Academic Press, San Diego
16. Bramblett, R. D., Panu, A. M., Ballesteros, J. A., and Reggio, P. H. (1995) Construction of a 3D model of the cannabinoid CB1 receptor: determination of helix ends and helix orientation. Life Sci. 56, 1971-1982
17. Ripka, A., Shapiro, G., and Chesworth, R. (January 14, 2010) U. S. Patent WO2010/006130
18. Okazaki, K., Uchida, M., Mukaiyama, H., Kobayashi, H., Kai, Y., Takeuchi, H., Yokoyama, K., Terao, Y., Hoyano, Y., Shiohara, H., and Kikuchi, N. (July 30, 2003) Patent EP1331221A1
19. Al-Awar, R. S., Hecker, K. A., Ray, J. E., Huang, J., Joseph, S., Li, T., Paal, M., Rathnachalam, R., Shih, C., Wald, P. P., Zhou, X., and Zhu, G. (December 11, 2003) U. S. Patent 2003/0229026 A1
20. Pelcman, B., Olofsson, K., Katkevics, M., Ozola, V., Suna, E., Kalvins, I., Trapencieris, P., Katkevica, D., and Schaal, W. (February 2, 2006) U. S. Patent Application 20120029016 A1
21. McAllister, S. D., Hurst, D. P., Barnett-Norris, J., Lynch, D., Reggio, P. H., and Abood, M. E. (2004) Structural mimicry in class A G protein-coupled receptor rotamer toggle switches: the importance of the F3.36(201)/W6.48(357) interaction in cannabinoid CB1 receptor activation. J. Biol. Chem. 279, 48024-48037 (Pubitemid 39540955)
22. McAllister, S. D., Rizvi, G., Anavi-Goffer, S., Hurst, D. P., Barnett-Norris, J., Lynch, D. L., Reggio, P. H., and Abood, M. E. (2003) An aromatic microdomain at the cannabinoid CB(1) receptor constitutes an agonist/inverse agonist binding region. J. Med. Chem. 46, 5139-5152 (Pubitemid 37414184)
23. Kotsikorou, E., Madrigal, K. E., Hurst, D. P., Sharir, H., Lynch, D. L., Heynen-Genel, S., Milan, L. B., Chung, T. D., Seltzman, H. H., Bai, Y., Caron, M. G., Barak, L., Abood, M. E., and Reggio, P. H. (2011) Identification of the GPR55 agonist binding site using a novel set of high-potency GPR55 selective ligands. Biochemistry 50, 5633-5647
24. Fay, J. F., and Farrens, D. L. (2012) A key agonist-induced conformational change in the cannabinoid receptor CB1 is blocked by the allosteric ligand org 27569. J. Biol. Chem. 287, 33873-33882
25. Marcu, J., Shore, D. M., Kapur, A., Trznadel, M., Makriyannis, A., Reggio, P. H., and Abood, M. E. (2013) Novel insights into CB1 cannabinoid receptor signaling: a key interaction identified between EC3-loop and TMH2. J. Pharmacol. Exp. Ther. 345, 189-197
26. Hurst, D. P., Lynch, D. L., Barnett-Norris, J., Hyatt, S. M., Seltzman, H. H., Zhong, M., Song, Z. H., Nie, J., Lewis, D., and Reggio, P. H. (2002) N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1-H- pyrazole-3-carboxamide (SR141716A) interaction with LYS 3.28(192) is crucial for its inverse agonism at the cannabinoid CB1 receptor. Mol. Pharmacol. 62, 1274-1287 (Pubitemid 35403823)
27. Hurst, D., Umejiego, U., Lynch, D., Seltzman, H., Hyatt, S., Roche, M., McAllister, S., Fleischer, D., Kapur, A., Abood, M., Shi, S., Jones, J., Lewis, D., and Reggio, P. (2006) Biarylpyrazole inverse agonists at the cannabinoid CB1 receptor: importance of the C-3 carboxamide oxygen/lysine3.28(192) interaction. J. Med. Chem. 49, 5969-5987 (Pubitemid 44484943)
28. Ahn, K. H., Mahmoud, M. M., Shim, J. Y., and Kendall, D. A. (2013) Distinct roles of β-arrestin 1 and β-arrestin 2 in ORG27569-induced biased signaling and internalization of the cannabinoid receptor one (CB1). J. Biol. Chem. 288, 9790-9800
29. Fiser, A., Do, R. K., and Sali, A. (2000) Modeling of loops in protein structures. Protein Sci. 9, 1753-1773
30. Sali, A., and Blundell, T. L. (1993) Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol. 234, 779-815 (Pubitemid 24007801)
31. Ahn, K. H., Pellegrini, M., Tsomaia, N., Yatawara, A. K., Kendall, D. A., and Mierke, D. F. (2009) Structural analysis of the human cannabinoid receptor one carboxyl terminus identifies two amphipathic helices. Biopolymers 91, 565-573
32. Piscitelli, F., Ligresti, A., La Regina, G., Coluccia, A., Morera, L., Allarà, M., Novellino, E., Di Marzo, V., and Silvestri, R. (2012) Indole-2-carboxamides as allosteric modulators of the cannabinoid CB(1) receptor. J. Med. Chem. 55, 5627-5631
33. Song, Z. H., and Bonner, T. I. (1996) A lysine residue of the cannabinoid receptor is critical for receptor recognition by several agonists but not WIN55212-2. Mol. Pharmacol. 49, 891-896
34. Ambrosio, C., Molinari, P., Cotecchia, S., and Costa, T. (2000) Catecholbinding serines of β(2)-adrenergic receptors control the equilibrium between active and inactive receptor states. Mol. Pharmacol. 57, 198-210 (Pubitemid 30033276)
35. Kapur, A., Hurst, D. P., Fleischer, D., Whitnell, R., Thakur, G. A., Samaniego, P., Makriyannis, A., Reggio, P. H., and Abood, M. E. (2007) Mutation studies of Ser7.39 and Ser2.60 in the human CB1 receptor: evidence for a serine-induced bend in cb1 transmembrane helix 7. Mol. Pharmacol. 71, 1512-1524 (Pubitemid 47010904)
36. Ahn, K. H., Bertalovitz, A. C., Mierke, D. F., and Kendall, D. A. (2009) Dual role of the second extracellular loop of the cannabinoid receptor 1: ligand binding and receptor localization. Mol. Pharmacol. 76, 833-842
37. Bertalovitz, A. C., Ahn, K. H., and Kendall, D. A. (2010) Ligand binding sensitivity of the extracellular loop two of the cannabinoid receptor 1. Drug Dev. Res. 71, 404-411
38. Gregory, K. J., Sexton, P. M., and Christopoulos, A. (2007) Allosteric modulation of muscarinic acetylcholine receptors. Curr. Neuropharmacol. 5, 157-167 (Pubitemid 351863857)
39. Wess, J. (1993) Mutational analysis of muscarinic acetylcholine receptors: structural basis of ligand/receptor/G protein interactions. Life Sci. 53, 1447-1463
40. Birdsall, N. J., Lazareno, S., and Matsui, H. (1996) Allosteric regulation of muscarinic receptors. Prog. Brain Res. 109, 147-151 (Pubitemid 27047082)
41. Wess, J. (2005) Allosteric binding sites on muscarinic acetylcholine receptors. Mol. Pharmacol. 68, 1506-1509
42. Hurst, D. P., Grossfield, A., Lynch, D. L., Feller, S., Romo, T. D., Gawrisch, K., Pitman, M. C., and Reggio, P. H. (2010) A lipid pathway for ligand binding is necessary for a cannabinoid G protein-coupled receptor. J. Biol. Chem. 285, 17954-17964
43. Hanson, M. A., Roth, C. B., Jo, E., Griffith, M. T., Scott, F. L., Reinhart, G., Desale, H., Clemons, B., Cahalan, S. M., Schuerer, S. C., Sanna, M. G., Han, G. W., Kuhn, P., Rosen, H., and Stevens, R. C. (2012) Crystal structure of a lipid G protein-coupled receptor. Science 335, 851-855
44. Keov, P., Sexton, P. M., and Christopoulos, A. (2011) Allosteric modulation of G protein-coupled receptors: a pharmacological perspective. Neuropharmacology 60, 24-35
45. Schwartz, T. W., and Holst, B. (2007) Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act? Trends Pharmacol. Sci. 8, 366-373 (Pubitemid 47087971)
46. Peeters, M. C., Wisse, L. E., Dinaj, A., Vroling, B., Vriend, G., and Ijzerman, A. P. (2012) The role of the second and third extracellular loops of the adenosine A1 receptor in activation and allosteric modulation. Biochem. Pharmacol. 84, 76-87
47. Huang, X. P., and Ellis, J. (2007) Mutational disruption of a conserved disulfide bond in muscarinic acetylcholine receptors attenuates positive homotropic cooperativity between multiple allosteric sites and has subtype-dependent effects on the affinities of muscarinic allosteric ligands. Mol. Pharmacol. 71, 759-768
48. Peeters, M. C., van Westen, G. J., Li, Q., and IJzerman, A. P. (2011) Importance of the extracellular loops in G protein-coupled receptors for ligand recognition and receptor activation. Trends Pharmacol. Sci. 32, 35-42
49. Ahuja, S., Hornak, V., Yan, E. C., Syrett, N., Goncalves, J. A., Hirshfeld, A., Ziliox, M., Sakmar, T. P., Sheves, M., Reeves, P. J., Smith, S. O., and Eilers, M. (2009) Helix movement is coupled to displacement of the second extracellular loop in rhodopsin activation. Nat. Struct. Mol. Biol. 16, 168-175
50. Unal, H., Jagannathan, R., Bhat, M. B., and Karnik, S. S. (2010) Ligand-specific conformation of extracellular loop-2 in the angiotensin II type 1 receptor. J. Biol. Chem. 285, 16341-16350
51. Unal, H., Jagannathan, R., Bhatnagar, A., Tirupula, K., Desnoyer, R., and Karnik, S. S. (2013) Long range effect of mutations on specific conformational changes in the extracellular loop 2 of angiotensin II type 1 receptor. J. Biol. Chem. 288, 540-551
52. Banères, J. L., Mesnier, D., Martin, A., Joubert, L., Dumuis, A., and Bockaert, J. (2005) Molecular characterization of a purified 5-HT4 receptor: a structural basis for drug efficacy. J. Biol. Chem. 280, 20253-20260 (Pubitemid 40776722)
53. Rana, S., and Baranski, T. J. (2010) Third extracellular loop (EC3)-N terminus interaction is important for seven-transmembrane domain receptor function: implications for an activation microswitch region. J. Biol. Chem. 285, 31472-31483
54. Décaillot, F. M., Befort, K., Filliol, D., Yue, S., Walker, P., and Kieffer, B. L. (2003) Opioid receptor random mutagenesis reveals a mechanism for G protein-coupled receptor activation. Nat. Struct. Biol. 10, 629-636 (Pubitemid 36944716)
55. Hamm, H. E., Deretic, D., Arendt, A., Hargrave, P. A., Koenig, B., and Hofmann, K. P. (1988) Site of G protein binding to rhodopsin mapped with synthetic peptides from the α subunit. Science 241, 832-835
56. Schwartz, T. W., Frimurer, T. M., Holst, B., Rosenkilde, M. M., and Elling, C. E. (2006) Molecular mechanism of 7TM receptor activation-a global toggle switch model. Annu. Rev. Pharmacol. Toxicol. 46, 481-519 (Pubitemid 43271198)