Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs

Nature

Volumn 503, Issue 7475, 2013, Pages 295-299

  Dror, Ron O ^a   Green, Hillary F ^a   Valant, Celine ^b   Borhani, David W ^a   Valcourt, James R ^a   Pan, Albert C ^a   Arlow, Daniel H ^a   Canals, Meritxell ^b   Lane, J Robert ^b   Rahmani, Raphaël ^b   Baell, Jonathan B ^b   Sexton, Patrick M ^b   Christopoulos, Arthur ^b   Shaw, David E ^a,c  

^a D E SHAW RESEARCH   (United States)

^b MONASH UNIVERSITY   (Australia)

^c Och Spine at New York Presbyterian Hospitals   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALCURONIUM; G PROTEIN COUPLED RECEPTOR; GALLAMINE; MUSCARINIC M2 RECEPTOR; RADIOLIGAND; STRYCHNINE;

DRUG; LIGAND; PROTEIN; RESEARCH;

ALLOSTERISM; ANIMAL CELL; ARTICLE; BINDING SITE; CHEMICAL MODIFICATION; CONFORMATIONAL TRANSITION; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG RECEPTOR BINDING; LIGAND BINDING; MOLECULAR DYNAMICS; NONHUMAN; PRIORITY JOURNAL; STATIC ELECTRICITY;

ALLOSTERIC REGULATION; ANIMALS; BINDING SITES; CHO CELLS; CRICETULUS; DRUG DESIGN; HUMANS; MODELS, CHEMICAL; MOLECULAR CONFORMATION; MOLECULAR DYNAMICS SIMULATION; MUTATION; PROTEIN BINDING; RECEPTORS, G-PROTEIN-COUPLED; REPRODUCIBILITY OF RESULTS;

EID: 84887620421     PISSN: 00280836     EISSN: 14764687     Source Type: Journal    
DOI: 10.1038/nature12595     Document Type: Article

References (52)

1. Conn, P. J., Jones, C. K. & Lindsley, C. W. Subtype selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders. Trends Pharmacol. Sci. 30, 148-155 (2009).
2. Keov, P., Sexton, P. M. & Christopoulos, A. Allosteric modulation of G protein-coupled receptors: apharmacologicalperspective. Neuropharmacology 60, 24-35 (2011).
3. Filmore, D. It's a GPCR world. Modern Drug Discov. 7, 24-28 (2004).
4. Jakubik, J. & El-Fakahany, E. E. Allosteric modulation of muscarinic acetylcholine receptors. Pharmaceuticals 3, 2838-2860 (2010).
5. Haga, K. et al. Structure of human M2 muscarinic acetylcholine receptor bound to an antagonist. Nature 482, 547-551 (2012).
6. Liu, W. et al. Structural basis for allosteric regulation of GPCRs by sodium ions. Science 6091, 232-236 (2012).
7. 2 adrenergic receptor-Gs protein complex. Nature 477, 549-555 (2011).
8. Lazareno, S. & Birdsall, N. J. Detection, quantitation, and verification of allosteric interactions of agents with labeled and unlabeled ligands at G protein-coupled receptors: interactions of strychnine and acetylcholine at muscarinic receptors. Mol. Pharmacol. 48, 362-378 (1995).
9. Dror, R. O. et al. Pathway and mechanism of drug binding to G-protein-coupled receptors. Proc. Natl Acad. Sci. USA 108, 13118-13123 (2011).
10. Shan, Y. et al. How does a drug molecule find its target binding site? J. Am. Chem. Soc. 133, 9181-9183 (2011).
11. Buch, I., Giorgino, T. & De Fabritiis, G. Complete reconstruction of an enzyme-inhibitor binding process by molecular dynamics simulations. Proc. Natl Acad. Sci. USA 108, 10184-10189 (2011).
12. 422Trp in a cryptical cluster of amino acids for baseline affinity, subtype selectivity, and cooperativity. Mol. Pharmacol. 70, 181-193 (2006).
13. Huang, X.-P., Prilla, S., Mohr, K. & Ellis, J. Critical amino acid residues of the common allosteric site on the M2 muscarinic acetylcholine receptor. Mol. Pharmacol. 68, 769-778 (2005).
14. May, L. T. et al. Structure-function studies of allosteric agonism at M2 muscarinic acetylcholine receptors. Mol. Pharmacol. 72, 463-476 (2007).
15. 3H]dimethyl-W84at the common allosteric site ofmuscarinic M2receptors. Mol. Pharmacol. 64, 180-190 (2003).
16. Ballesteros, J. & Weinstein, H. Integrated methods for the construction of three-dimensional models and computational probing ofstructure-function relations in G-protein-coupled receptors. Methods Neurosci. 25, 366-428 (1995).
17. Matsui, H., Lazareno, S. & Birdsall, N. J. Probing of the location of the allosteric site on m1 muscarinic receptors by site-directed mutagenesis. Mol. Pharmacol. 47, 88-98 (1995).
18. 1 muscarinic acetylcholine receptor achieved by allosteric potentiation. Proc. Natl Acad. Sci. USA 106, 15950-15955 (2009).
19. 2 receptors: synthesis, allosteric potency, and positive cooperativity of silicon-based W84 derivatives. Organometallics 21, 803-811 (2002).
20. Choe, H. W. et al. Crystal structure of metarhodopsin II. Nature 471, 651-655 (2011).
21. Bock, A. et al. The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling. Nat. Commun. 3, 1044 (2012).
22. Shoichet, B. & Kobilka, B. Structure-based drug screening for G-protein-coupled receptors. Trends Pharmacol. Sci. 33, 268-272 (2012).
23. Totrov, M. & Abagyan, R. Flexible ligand docking to multiple receptor conformations: a practical alternative. Curr. Opin. Struct. Biol. 18, 178-184 (2008).
24. Avlani, V., May, L. T., Sexton, P. M. & Christopoulos, A. Application of a kinetic model to the apparently complex behavior of negative and positive allosteric modulators of muscarinic acetylcholine receptors. J. Pharmacol. Exp. Ther. 308, 1062-1072 (2004).
25. 3 adenosine receptor. Mol. Pharmacol. 63, 1021-1031 (2003).
26. Silvano, E. et al. The tetrahydroisoquinoline derivative SB269, 652 is an allosteric antagonist at dopamine D3 and D2 receptors. Mol. Pharmacol. 78, 925-934 (2010).
27. Lazareno, S., Popham, A. & Birdsall, N. J. Analogs of WIN 62, 577 define a second allosteric site on muscarinic receptors. Mol. Pharmacol. 62, 1492-1505 (2002).
28. Yanamala, N. & Klein-Seetharaman, J. Allosteric modulation of G protein coupled receptors by cytoplasmic, transmembrane, and extracellular ligands. Pharmaceuticals 3, 3324-3342 (2010).
29. Shaw, D. E. et al. Millisecond-scale molecular dynamics simulation on Anton. In Proceedings of the Conference on High Performance Computing, Networking, Storage, and Analysis (ACM Press, 2009); available at http://dl.acm.org/citation.cfm?id51654099 (2009).
30. MacKerell, A. D. et al. All-atom empirical potential for molecular modeling and dynamics studies of proteins. J. Phys. Chem. B 102, 3586-3616 (1998).
31. Dror, R. O. et al. Identification of two distinct inactive conformations of the b2-adrenergic receptor reconciles structural and biochemical observations. Proc. Natl Acad. Sci. USA 106, 4689-4694 (2009).
32. Fahmy, K. et al. Protonation states of membrane-embedded carboxylic acid groups in rhodopsin and metarhodopsin II: a Fourier-transform infrared spectroscopy study of site-directed mutants. Proc. Natl Acad. Sci. USA 90, 10206-10210 (1993).
33. Everett, A. J., Openshaw, H. T. & Smith, G. F. The constitution of aspidospermine. Part III. Reactivity at the nitrogen atoms, and biogenetic considerations. J. Chem. Soc. 1120-1123 (1957).
34. Rosenbaum, D. M. et al. Structure and function of an irreversible agonist-b2 adrenoceptor complex. Nature 469, 236-240 (2011).
35. Kruse, A. et al. Structure and dynamics of the M3 muscarinic acetylcholine receptor. Nature 482, 552-556 (2012).
36. Shaw, D. E. et al. Atomic-level characterization of the structural dynamics of proteins. Science 330, 341-346 (2010).
37. Kräutler, V., van Gunsteren, W. F. & Hünenberger, P. H. A fast SHAKE algorithm to solve distance constraint equations for small molecules in molecular dynamics simulations. J. Comput. Chem. 22, 501-508 (2001).
38. Tuckerman, M., Berne, B. J. & Martyna, G. J. Reversible multiple time scale molecular dynamics. J. Chem. Phys. 97, 1990-2001 (1992).
39. Shan, Y., Klepeis, J. L., Eastwood, M. P., Dror, R. O. & Shaw, D. E. Gaussian split Ewald: a fast Ewald mesh method for molecular simulation. J. Chem. Phys. 122, 54101 (2005).
40. 2O. J. Cryst. Spectroscop. Res. 15, 453-471 (1985).
41. DeLano, W. L. The PyMOL Molecular Graphics System v. 1. 5. 0. 3-01 (Schrödinger, LLC, New York, New York, 2012).
42. Mackerell, A. D. Jr, Feig, M. & Brooks, C. L. III. Extending the treatment of backbone energetics in protein force fields: limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations. J. Comput. Chem. 25, 1400-1415 (2004).
43. Piana, S., Lindorff-Larsen, K. & Shaw, D. E. How robust are protein folding simulations with respect to force field parameterization? Biophys. J. 100, L47-L49 (2011).
44. Klauda, J. B. et al. Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types. J. Phys. Chem. B 114, 7830-7843 (2010).
45. Vanommeslaeghe, K. et al. CHARMM general force field: a force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J. Comput. Chem. 31, 671-690 (2010).
46. Caldwell, J. & Kollman, P. Cation-p interactions: nonadditive effects are critical in their accurate representation. J. Am. Chem. Soc. 117, 4177-4178 (1995).
47. Schneider, H. et al. Host-guest supramolecular chemistry. 34. The incremental approach to noncovalent interactions: Coulomb and van der Waals effects in organic ion pairs. J. Am. Chem. Soc. 20, 7698-7703 (1991).
48. Humphrey, W., Dalke, A. & Schulten, K. VMD: visual molecular dynamics. J. Mol. Graph. 14, 33-38 (1996).
49. Baker, N. A., Sept, D., Joseph, S., Holst, M. J. & McCammon, J. A. Electrostatics of nanosystems: application to microtubules and the ribosome. Proc. Natl Acad. Sci. USA 98, 10037-10041 (2001).
50. Gnagey, A. L., Seidenberg, M. & Ellis, J. Site-directed mutagenesis reveals two epitopes involved in the subtype selectivity of the allosteric interactions of gallamine at muscarinic acetylcholine receptors. Mol. Pharmacol. 56, 1245-1253 (1999).
51. 5 subtype selectivities of some structurally diverse allosteric ligands in N-methylscopolamine-occupied receptors. Mol. Pharmacol. 64, 21-31 (2003).
52. Avlani, V. A. et al. Critical role for the second extracellular loopin the bindingof both orthosteric and allosteric G protein-coupled receptor ligands. J. Biol. Chem. 282, 25677-25686 (2007).