Molecular mechanisms of bitopic ligand engagement with the M1 muscarinic acetylcholine receptor

Journal of Biological Chemistry

Volumn 289, Issue 34, 2014, Pages 23817-23837

  Keov, Peter ^a   López, Laura ^a   Devine, Shane M ^a   Valant, Celine ^a   Lane, J Robert ^a   Scammells, Peter J ^a   Sexton, Patrick M ^a   Christopoulos, Arthur ^a  

^a MONASH UNIVERSITY   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

ENZYME ACTIVITY; MOLECULAR MODELING;

INTRACELLULAR CALCIUM MOBILIZATION; MOLECULAR MECHANISM; MUSCARINIC ACETYLCHOLINE RECEPTORS; MUSCARINIC ACETYLCHOLINE RECEPTORS (MACHR); PROTEIN COUPLED RECEPTORS; RECEPTOR ACTIVATION; SITE DIRECTED MUTAGENESIS; TRANSMEMBRANE HELICES;

LIGANDS;

1 [1 CYCLOHEXYLPIPERIDIN 4 YL] 1H BENZ[D]IMIDAZOL 2(3H) ONE; 1 [1' (2 METHYLBENZYL) 1,4' BIPIPERIDIN 4 YL] 1H BENZ[D]IMIDAZOL 2(3H) ONE; 1 [3 (4 BUTYL 1 PIPERIDINYL)PROPYL] 3,4 DIHYDRO 2(1H) QUINOLINONE; ATROPINE; CALCIUM ION; CHOLINERGIC RECEPTOR AFFECTING AGENT; CHOLINERGIC RECEPTOR STIMULATING AGENT; G PROTEIN COUPLED RECEPTOR; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; MUSCARINIC AGENT; MUSCARINIC M1 RECEPTOR; MUSCARINIC M1 RECEPTOR AGONIST; UNCLASSIFIED DRUG; VCP 794; VCP 813; XANOMELINE; LIGAND; MUSCARINIC RECEPTOR; PRIMER DNA;

ARTICLE; BINDING AFFINITY; BINDING SITE; BITOPIC LIGAND BINDING; CALCIUM MOBILIZATION; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG MECHANISM; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG STRUCTURE; ENZYME PHOSPHORYLATION; LIGAND BINDING; MOLECULAR MODEL; MUTANT; MUTATION; ORTHOSTERIC BINDING SITE; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN STRUCTURE; SECOND EXTRACELLULAR LOOP; SITE DIRECTED MUTAGENESIS; STRUCTURE ACTIVITY RELATION; TRANSMEMBRANE HELICAL DOMAIN 2; TRANSMEMBRANE HELICAL DOMAIN 3; TRANSMEMBRANE HELICAL DOMAIN 7; WILD TYPE; CHEMICAL STRUCTURE; DRUG EFFECTS; FLOW CYTOMETRY; METABOLISM; NUCLEOTIDE SEQUENCE; PHOSPHORYLATION;

ALLOSTERIC SITE; BASE SEQUENCE; DNA PRIMERS; FLOW CYTOMETRY; LIGANDS; MODELS, MOLECULAR; MUSCARINIC AGONISTS; PHOSPHORYLATION; RECEPTORS, MUSCARINIC;

EID: 84906539125     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M114.582874     Document Type: Article

References (62)

1. Bodick, N. C., Offen, W. W., Levey, A. I., Cutler, N. R., Gauthier, S. G., Satlin, A., Shannon, H. E., Tollefson, G. D., Rasmussen, K., Bymaster, F. P., Hurley, D. J., Potter, W. Z., and Paul, S. M. (1997) Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch. Neurol. 54, 465-473
2. Shekhar, A., Potter, W. Z., Lightfoot, J., Lienemann, J., Dubé, S., Mallinckrodt, C., Bymaster, F. P., McKinzie, D. L., and Felder, C. C. (2008) Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am. J. Psychiatry 165, 1033-1039
3. Langmead, C. J., Watson, J., and Reavill, C. (2008) Muscarinic acetylcholine receptors as CNS drug targets. Pharmacol. Ther. 117, 232-243
4. Keov, P., Sexton, P. M., and Christopoulos, A. (2011) Allosteric modulation of G protein-coupled receptors: a pharmacological perspective. Neuropharmacology 60, 24-35
5. Ma, L., Seager, M. A., Seager, M., Wittmann, M., Jacobson, M., Bickel, D., Burno, M., Jones, K., Graufelds, V. K., Xu, G., Pearson, M., McCampbell, A., Gaspar, R., Shughrue, P., Danziger, A., Regan, C., Flick, R., Pascarella, D., Garson, S., Doran, S., Kreatsoulas, C., Veng, L., Lindsley, C. W., Shipe, W., Kuduk, S., Sur, C., Kinney, G., Seabrook, G. R., and Ray, W. J. (2009) Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation. Proc. Natl. Acad. Sci. U.S.A. 106, 15950-15955
6. Marlo, J. E., Niswender, C. M., Days, E. L., Bridges, T. M., Xiang, Y., Rodriguez, A. L., Shirey, J. K., Brady, A. E., Nalywajko, T., Luo, Q., Austin, C. A., Williams, M. B., Kim, K., Williams, R., Orton, D., Brown, H. A., Lindsley, C. W., Weaver, C. D., and Conn, P. J. (2009) Discovery and characterization of novel allosteric potentiators of M1 muscarinic receptors reveals multiple modes of Activity. Mol. Pharmacol. 75, 577-588
7. Jones, C. K., Brady, A. E., Davis, A. A., Xiang, Z., Bubser, M., Tantawy, M. N., Kane, A. S., Bridges, T. M., Kennedy, J. P., Bradley, S. R., Peterson, T. E., Ansari, M. S., Baldwin, R. M., Kessler, R. M., Deutch, A. Y., Lah, J. J., Levey, A. I., Lindsley, C. W., and Conn, P. J. (2008) Novel selective allosteric activator of the M1 muscarinic acetylcholine receptor regulates amyloid processing and produces antipsychotic-like activity in rats. J. Neurosci. 28, 10422-10433
8. Langmead, C. J., Austin, N. E., Branch, C. L., Brown, J. T., Buchanan, K. A., Davies, C. H., Forbes, I. T., Fry, V. A., Hagan, J. J., Herdon, H. J., Jones, G. A., Jeggo, R., Kew, J. N., Mazzali, A., Melarange, R., Patel, N., Pardoe, J., Randall, A. D., Roberts, C., Roopun, A., Starr, K. R., Teriakidis, A., Wood, M. D., Whittington, M., Wu, Z., and Watson, J. (2008) Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist 77-LH-28-1. Br. J. Pharmacol. 154, 1104-1115
9. Budzik, B., Garzya, V., Shi, D., Walker, G., Woolley-Roberts, M., Pardoe, J., Lucas, A., Tehan, B., Rivero, R. A., Langmead, C. J., Watson, J., Wu, Z., Forbes, I. T., Jin, J. (2010) Novel N-substituted benzimidazolones as potent, selective, CNS-penetrant, and orally active M1 mAChR agonists. ACS Med. Chem. Lett. 1, 244-248
10. Gregory, K. J., Hall, N. E., Tobin, A. B., Sexton, P. M., and Christopoulos, A. (2010) Identification of orthosteric and allosteric site Mutations in M2 muscarinic acetylcholine receptors that contribute to ligand-selective signaling bias. J. Biol. Chem. 285, 7459-7474
11. Sur, C., Mallorga, P. J., Wittmann, M., Jacobson, M. A., Pascarella, D., Williams, J. B., Brandish, P. E., Pettibone, D. J., Scolnick, E. M., and Conn, P. J. (2003) N-Desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-Aspartate receptor activity. Proc. Natl. Acad. Sci. U.S.A. 100, 13674-13679
12. Spalding, T. A., Ma, J. N., Ott, T. R., Friberg, M., Bajpai, A., Bradley, S. R., Davis, R. E., Brann, M. R., and Burstein, E. S. (2006) Structural requirements of transmembrane domain 3 for activation by the M1 muscarinic receptor agonists AC-42, AC-260584, clozapine, and N-desmethylclozapine: evidence for three distinct modes of receptor activation. Mol. Pharmacol. 70, 1974-1983
13. Antony, J., Kellershohn, K., Mohr-Andrä, M., Kebig, A., Prilla, S., Muth, M., Heller, E., Disingrini, T., Dallanoce, C., Bertoni, S., Schrobang, J., Tränkle, C., Kostenis, E., Christopoulos, A., Höltje, H. D., Barocelli, E., De Amici, M., Holzgrabe, U., and Mohr, K. (2009) Dualsteric GPCR targeting: a novel route to binding and signaling pathway selectivity. FASEB J. 23, 442-450
14. Valant, C., Gregory, K. J., Hall, N. E., Scammells, P. J., Lew, M. J., Sexton, P. M., and Christopoulos, A. (2008) A novel mechanism of G proteincoupled receptor functional selectivity. J. Biol. Chem. 283, 29312-29321
15. Avlani, V. A., Langmead, C. J., Guida, E., Wood, M. D., Tehan, B. G., Herdon, H. J., Watson, J. M., and Sexton, P. M. (2010) Orthosteric and allosteric modes of interaction of novel selective agonists of the M1 muscarinic acetylcholine receptor. Mol. Pharmacol. 78, 94-104
16. Narlawar, R., Lane, J. R., Doddareddy, M., Lin, J., Brussee, J., and Ijzerman, A. P. (2010) Hybrid ortho/allosteric ligands for the adenosine A1 receptor. J. Med. Chem. 53, 3028-3037
17. Disingrini, T., Muth, M., Dallanoce, C., Barocelli, E., Bertoni, S., Keller- shohn, K., Mohr, K., De Amici, M., and Holzgrabe, U. (2006) Design, synthesis, and action of oxotremorine-related hybrid-type allosteric modulators of muscarinic acetylcholine receptors. J. Med. Chem. 49, 366-372
18. Steinfeld, T., Mammen, M., Smith, J. A., Wilson, R. D., and Jasper, J. R. (2007) A novel multivalent ligand that bridges the allosteric and orthosteric binding sites of the M2 muscarinic receptor. Mol. Pharmacol. 72, 291-302
19. Keov, P., Valant, C., Devine, S. M., Lane, J. R., Scammells, P. J., Sexton, P. M., and Christopoulos, A. (2013) Reverse engineering of the selective agonist TBPB unveils both orthosteric and allosteric modes of action at the M1 muscarinic acetylcholine receptor. Mol. Pharmacol. 84, 425-437
20. Gregory, K. J., Sexton, P. M., Tobin, A. B., and Christopoulos, A. (2012) Stimulus bias provides evidence for conformational constraints in the structure of a G protein-coupled receptor. J. Biol. Chem. 287, 37066-37077
21. May, L. T., Avlani, V. A., Langmead, C. J., Herdon, H. J., Wood, M. D., Sexton, P. M., and Christopoulos, A. (2007) Structure-function studies of allosteric agonism at M2 muscarinic acetylcholine receptors. Mol. Pharmacol. 72, 463-476
22. Lebon, G., Langmead, C. J., Tehan, B. G., and Hulme, E. C. (2009) Mutagenic mapping suggests a novel binding mode for selective agonists of M1 muscarinic acetylcholine receptors. Mol. Pharmacol. 75, 331-341
23. Jacobson, M. A., Kreatsoulas, C., Pascarella, D. M., O'Brien, J. A., Sur, C. (2010) The M1 muscarinic receptor allosteric agonists AC-42 and 1-[1′- (2-methylbenzyl)-1,4′-bipiperidin-4-yl]-1,3-dihydro-2H-benzimidazol- 2-one bind to a unique site distinct from the acetylcholine orthosteric site. Mol. Pharmacol. 78, 648-657
24. Ward, S. D., Curtis, C. A., and Hulme, E. C. (1999) Alanine-scanning mutagenesis of transmembrane domain 6 of the M1 muscarinic acetylcholine receptor suggests That Tyr381 plays key roles in receptor function. Mol. Pharmacol. 56, 1031-1041
25. Spalding, T. A., Birdsall, N. J., Curtis, C. A., and Hulme, E. C. (1994) Acetylcholine mustard labels the binding site aspartate in muscarinic acetylcholine receptors. J. Biol. Chem. 269, 4092-4097
26. Lu, Z. L., and Hulme, E. C. (1999) The functional topography of transmembrane domain 3 of the M1 muscarinic acetylcholine receptor, revealed by scanning mutagenesis. J. Biol. Chem. 274, 7309-7315
27. Lebois, E. P., Bridges, T. M., Lewis, L. M., Dawson, E. S., Kane, A. S., Xiang, Z., Jadhav, S. B., Yin, H., Kennedy, J. P., Meiler, J., Niswender, C. M., Jones, C. K., Conn, P. J., Weaver, C. D., and Lindsley, C. W. (2010) Discovery and characterization of novel subtype-selective allosteric agonists for the investigation of M1 receptor function in the central nervous system. ACS Chem. Neurosci. 1, 104-121
28. Matsui, H., Lazareno, S., and Birdsall, N. J. (1995) Probing of the location of the allosteric site onm1muscarinic receptors by site-directed mutagenesis. Mol. Pharmacol. 47, 88-98
29. Nawaratne, V., Leach, K., Suratman, N., Loiacono, R. E., Felder, C. C., Armbruster, B. N., Roth, B. L., Sexton, P. M., and Christopoulos, A. (2008) New insights into the function of M4 muscarinic acetylcholine receptors gained using a novel allosteric modulator and a DREADD (designer receptor exclusively activated by a designer drug). Mol. Pharmacol. 74, 1119-1131
30. Ballesteros, J. A., and Weinstein, H. (1995) Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations inGprotein-coupled receptors in Methods in Neurosciences (Sealfon, S. C., ed), Vol 25, pp. 366-428, Academic Press
31. Thompson, J. D., Gibson, T. J., Plewniak, F., Jeanmougin, F., and Higgins, D. G. (1997) The CLUSTAL-X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res. 25, 4876-4882
32. Kruse, A. C., Hu, J., Pan, A. C., Arlow, D. H., Rosenbaum, D. M., Rosemond, E., Green, H. F., Liu, T., Chae, P. S., Dror, R. O., Shaw, D. E., Weis, W. I., Wess, J., and Kobilka, B. K. (2012) Structure and dynamics of theM3 muscarinic acetylcholine receptor. Nature 482, 552-556
33. Sali, A., and Blundell, T. L. (1993) Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol. 234, 779-815
34. Duan, Y., Wu, C., Chowdhury, S., Lee, M. C., Xiong, G., Zhang, W., Yang, R., Cieplak, P., Luo, R., Lee, T., Caldwell, J., Wang, J., and Kollman, P. (2003) A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations. J. Comput. Chem. 24, 1999-2012
35. Wang, J., Wolf, R. M., Caldwell, J. W., Kollman, P. A., and Case, D. A. (2004) Development and testing of a general amber force field. J. Comput. Chem. 25, 1157-1174
36. Mansour, A., Meng, F., Meador-Woodruff, J. H., Taylor, L. P., Civelli, O., and Akil, H. (1992) Site-directed mutagenesis of the human dopamine D2 receptor. Eur. J. Pharmacol. 227, 205-214
37. Wang, C. D., Gallaher, T. K., and Shih, J. C. (1993) Site-directed mutagenesis of the serotonin 5-hydroxytrypamine2 receptor: identification of amino acids necessary for ligand binding and receptor activation. Mol. Pharmacol. 43, 931-940
38. Phillips, J. C., Braun, R., Wang, W., Gumbart, J., Tajkhorshid, E., Villa, E., Chipot, C., Skeel, R. D., Kalé, L., and Schulten, K. (2005) Scalable molecular dynamics with NAMD. J. Comput. Chem. 26, 1781-1802
39. MacKerell, A. D., Bashford, D., Bellott, M., Dunbrack, R. L., Evanseck, J. D., Field, M. J., Fischer, S., Gao, J., Guo, H., Ha, S., Joseph-McCarthy, D., Kuchnir, L., Kuczera, K., Lau, F. T., Mattos, C., Michnick, S., Ngo, T., Nguyen, D. T., Prodhom, B., Reiher, W. E., Roux, B., Schlenkrich, M., Smith, J. C., Stote, R., Straub, J., Watanabe, M., Wiórkiewicz-Kuczera, J., Yin, D., and Karplus, M. (1998) All-Atom empirical potential for molecular modeling and dynamics studies of proteins. J. Phys. Chem. B 102, 3586-3616
40. Patra, M., Karttunen, M., Hyvönen, M. T., Falck, E., Lindqvist, P., and Vattulainen, I. (2003) Molecular dynamics simulations of lipid bilayers: major artifacts due to truncating electrostatic interactions. Biophys. J. 84, 3636-3645
41. Black, J. W., and Leff, P. (1983) Operational models of pharmacological agonism. Proc. R. Soc. Lond. B Biol. Sci. 220, 141-162
42. Black, J. W., Leff, P., Shankley, N. P., and Wood, J. (1985) An operational model of pharmacological agonism: the effect of E/[A] curve shape on agonist dissociation constant estimation. Br. J. Pharmacol. 84, 561-571
43. Kenakin, T., Watson, C., Muniz-Medina, V., Christopoulos, A., and Novick, S. (2012) A simple method for quantifying functional selectivity and agonist bias. ACS Chem. Neurosci. 3, 193-203
44. Christopoulos, A. (1998) Assessing the distribution of parameters in models of ligand-receptor interaction: to log or not to log. Trends Pharmacol. Sci. 19, 351-357
45. Leach, K., Davey, A. E., Felder, C. C., Sexton, P. M., and Christopoulos, A. (2011) The role of transmembrane domain 3 in the actions of orthosteric, allosteric, and atypical agonists of the M4 muscarinic Acetylcholine receptor. Mol. Pharmacol. 79, 855-865
46. Voigtländer, U., Jöhren, K., Mohr, M., Raasch, A., Tränkle, C., Buller, S., Ellis, J., Höltje, H. D., and Mohr, K. (2003) Allosteric site on muscarinic acetylcholine receptors: identification of two amino acids in the muscarinic M2 receptor that account entirely for the M2/M5 subtype selectivities of some structurally diverse allosteric ligands in N-methylscopolamine- occupie. Mol. Pharmacol. 64, 21-31
47. Goodwin, J. A., Hulme, E. C., Langmead, C. J., and Tehan, B. G. (2007) Roof and floor of the muscarinic binding pocket: variations in the binding modes of orthosteric ligands. Mol. Pharmacol. 72, 1484-1496
48. Scarselli, M., Li, B., Kim, S. K., and Wess, J. (2007) Multiple residues in the second extracellular loop are critical for M3 muscarinic acetylcholine receptor activation. J. Biol. Chem. 282, 7385-7396
49. Haga, K., Kruse, A. C., Asada, H., Yurugi-Kobayashi, T., Shiroishi, M., Zhang, C., Weis, W. I., Okada, T., Kobilka, B. K., Haga, T., and Kobayashi, T. (2012) Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist. Nature 482, 547-551
50. Kruse, A. C., Ring, A. M., Manglik, A., Hu, J., Hu, K., Eitel, K., Hübner, H., Pardon, E., Valant, C., Sexton, P. M., Christopoulos, A., Felder, C. C., Gmeiner, P., Steyaert, J., Weis, W. I., Garcia, K. C., Wess, J., and Kobilka, B. K. (2013) Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature 504, 101-106
51. Bee, M. S., and Hulme, E. C. (2007) Functional analysis of transmembrane domain 2 of the M1 muscarinic acetylcholine receptor. J. Biol. Chem. 282, 32471-32479
52. Nathan, P. J., Watson, J., Lund, J., Davies, C. H., Peters, G., Dodds, C. M., Swirski, B., Lawrence, P., Bentley, G. D., O'Neill, B. V., Robertson, J., Watson, S., Jones, G. A., Maruff, P., Croft, R. J., Laruelle, M., and Bullmore, E. T. (2013) The potent M1 receptor allosteric agonist GSK1034702 improves episodic memory in humans in the nicotine abstinence model of cognitive dysfunction. Int. J. Neuropsychopharmacol. 16, 721-731
53. Bridges, T. M., Brady, A. E., Kennedy, J. P., Daniels, R. N., Miller, N. R., Kim, K., Breininger, M. L., Gentry, P. R., Brogan, J. T., Jones, C. K., Conn, P. J., and Lindsley, C. W. (2008) Synthesis and SAR of analogues of the M1 allosteric agonist TBPB. Part I: exploration of alternative benzyl and privileged structure moieties. Bioorg. Med. Chem. Lett. 18, 5439-5442
54. Kenakin, T., and Christopoulos, A. (2013) Signalling bias in new drug discovery: detection, quantification, and therapeutic impact. Nat. Rev. Drug Discov. 12, 205-216
55. Koole, C., Wootten, D., Simms, J., Savage, E. E., Miller, L. J., Christopoulos, A., and Sexton, P. M. (2012) Second extracellular loop of human glucagonlike peptide-1 receptor (GLP-1R) differentially regulates orthosteric but not allosteric agonist binding and function. J. Biol. Chem. 287, 3659-3673
56. Koole, C., Wootten, D., Simms, J., Miller, L. J., Christopoulos, A., and Sexton, P. M. (2012) Second extracellular loop of human glucagon-like peptide-1 receptor (GLP-1R) has a critical role in GLP-1 peptide binding and receptor activation. J. Biol. Chem. 287, 3642-3658
57. Tschammer, N., Bollinger, S., Kenakin, T., and Gmeiner, P. (2011) Histidine 6.55 is a major determinant of ligand-biased signaling in dopamine D2L receptor. Mol. Pharmacol. 79, 575-585
58. Leppik, R. A., Miller, R. C., Eck, M., and Paquet, J. L. (1994) Role of acidic amino acids in the allosteric modulation by gallamine of antagonist binding at the m2 muscarinic acetylcholine receptor. Mol. Pharmacol. 45, 983-990
59. Krejcí, A., and Tucek, S. (2001) Changes of cooperativity between Nmethylscopolamine and allosteric modulators alcuronium and gallamine induced by mutations of external loops of muscarinic M3 receptors. Mol. Pharmacol. 60, 761-767
60. Avlani, V. A., Gregory, K. J., Morton, C. J., Parker, M. W., Sexton, P. M., and Christopoulos, A. (2007) Critical role for the second extracellular loop in the binding of both orthosteric and allosteric G protein-coupled receptor ligands. J. Biol. Chem. 282, 25677-25686
61. Trumpp-Kallmeyer, S., Hoflack, J., Bruinvels, A., and Hibert, M. (1992) Modeling of G-protein-coupled receptors: application to dopamine, adrenaline, serotonin, acetylcholine, and mammalian opsin receptors. J. Med. Chem. 35, 3448-3462
62. Babaoglu, K., and Shoichet, B. K. (2006) Deconstructing fragment-based inhibitor discovery. Nat. Chem. Biol. 2, 720-723