Modeling GPCR active state conformations: The β 2-adrenergic receptor

Proteins: Structure, Function and Bioinformatics

Volumn 79, Issue 5, 2011, Pages 1441-1457

  Simpson, Lisa M ^a   Wall, Ian D ^b   Blaney, Frank E ^b   Reynolds, Christopher A ^a  

^a UNIVERSITY OF ESSEX   (United Kingdom)

^b GLAXOSMITHKLINE   (United Kingdom)

Author keywords

Agonist; Docking; Muscarinic receptor; Principle component analysis; Restrained molecular dynamics; Rigid core analysis; Selectivity; Virtual screening

Indexed keywords

ADRENALIN; BETA 2 ADRENERGIC RECEPTOR; CARMOTEROL; GUANINE NUCLEOTIDE BINDING PROTEIN; ISOPRENALINE; MEMBRANE PROTEIN; OPSIN; SALMETEROL; TRANSDUCIN; TRANSMEMBRANE HELIX 5; TRANSMEMBRANE HELIX 6; TRANSMEMBRANE HELIX 7; UNCLASSIFIED DRUG; ZINC;

ARTICLE; BINDING SITE; CARBOXY TERMINAL SEQUENCE; CRYSTAL STRUCTURE; MOLECULAR DOCKING; MOLECULAR INTERACTION; MOLECULAR MECHANICS; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN CONFORMATION; SITE DIRECTED MUTAGENESIS;

ADRENERGIC BETA-2 RECEPTOR AGONISTS; ADRENERGIC BETA-2 RECEPTOR ANTAGONISTS; ANIMALS; BINDING SITES; CATALYTIC DOMAIN; CATTLE; HUMANS; HYDROGEN BONDING; LIGANDS; MOLECULAR DYNAMICS SIMULATION; MUTAGENESIS, SITE-DIRECTED; OPSINS; PROTEIN CONFORMATION; RECEPTORS, ADRENERGIC, BETA-2; ZINC;

EID: 79954544003     PISSN: 08873585     EISSN: 10970134     Source Type: Journal    
DOI: 10.1002/prot.22974     Document Type: Article

References (118)

1. Lagerstrom MC, Schioth HB. Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov 2008; 7: 339-357.
2. Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC. High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 2007; 318: 1258-1265.
3. Jaakola VP, Griffith MT, Hanson MA, Cherezov V, Chien EY, Lane JR, Ijzerman AP, Stevens RC. The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science 2008; 322: 1211-1217.
4. Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK. Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature 2007; 450: 383-387.
5. Warne T, Serrano-Vega MJ, Baker JG, Moukhametzianov R, Edwards PC, Henderson R, Leslie AGW, Tate CG, Schertler GFX. Structure of a beta(1)-adrenergic G-protein-coupled receptor. Nature 2008; 454: 486-4U2.
6. Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le T, I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M. Crystal structure of rhodopsin: A G protein-coupled receptor. Science 2000; 289: 739-745.
7. Park JH, Scheerer P, Hofmann KP, Choe HW, Ernst OP. Crystal structure of the ligand-free G-protein-coupled receptor opsin. Nature 2008; 454: 183-187.
8. Scheerer P, Park JH, Hildebrand PW, Kim YJ, Krauss N, Choe HW, Hofmann KP, Ernst OP. Crystal structure of opsin in its G-protein-interacting conformation. Nature 2008; 455: 497-502.
9. Vogel R, Siebert F. Conformations of the active and inactive states of opsin. J Biol Chem 2001; 276: 38487-38493.
10. Surya A, Foster KW, Knox BE. Transducin activation by the bovine opsin apoprotein. J Biol Chem 1995; 270: 5024-5031.
11. Brown AD, Bunnage ME, Glossop PA, James K, Jones R, Lane CA, Lewthwaite RA, Mantell S, Perros-Huguet C, Price DA, Trevethick M, Webster R. The discovery of long acting beta2-adrenoreceptor agonists. Bioorg Med Chem Lett 2007; 17: 4012-4015.
12. Wallin A, Melander B, Rosenhall L, Sandstrom T, Wahlander L. Formoterol, a new long acting beta 2 agonist for inhalation twice daily, compared with salbutamol in the treatment of asthma. Brit Med J 1990; 45: 259.
13. Ullman A, Svedmyr N. Salmeterol, a new long acting inhaled beta 2 adrenoceptor agonist: comparison with salbutamol in adult asthmatic patients. Brit Med J 1988; 43: 674.
14. Svedmyr N. Fenoterol: a beta2-adrenergic agonist for use in asthma. Pharmacology, pharmacokinetics, clinical efficacy and adverse effects. Pharmacotherapy 1985; 5: 109-126.
15. McFadden ER, Jr. Aerosolized bronchodilators and steroids in the treatment of airway obstruction in adults. Am Rev Respir Dis 1980; 122: 89-96.
16. Kikkawa H, Kanno K, Ikezawa K. TA-2005, a novel, long-acting, and selective beta 2-adrenoceptor agonist: characterization of its in vivo bronchodilating action in guinea pigs and cats in comparison with other beta 2-agonists. Biol Pharm Bull 1994; 17: 1047-1052.
17. Altenbach C, Kusnetzow AK, Ernst OP, Hofmann KP, Hubbell WL. High-resolution distance mapping in rhodopsin reveals the pattern of helix movement due to activation. Proc Natl Acad Sci U S A 2008; 105: 7439-7444.
18. Farrens DL, Altenbach C, Yang K, Hubbell WL, Khorana HG. Requirement of rigid-body motion of transmembrane helices for light activation of rhodopsin. Science 1996; 274: 768-770.
19. Pierce KL, Premont RT, Lefkowitz RJ. Seven-transmembrane receptors. Nat Rev Mol Cell Biol 2002; 3: 639-650.
20. Schwartz TW, Rosenkilde MM. Is there a 'lock' for all agonist 'keys' in 7TM receptors? Trends Pharmacol Sci 1996; 17: 213-216.
21. Fritze O, Filipek S, Kuksa V, Palczewski K, Hofmann KP, Ernst OP. Role of the conserved NPxxY(x)5, 6F motif in the rhodopsin ground state and during activation. Proc Natl Acad Sci U S A 2003; 100: 2290-2295.
22. Knierim B, Hofmann KP, Ernst OP, Hubbell WL. Sequence of late molecular events in the activation of rhodopsin. Proc Natl Acad Sci U S A 2007; 104: 20290-20295.
23. Okada T, Ernst OP, Palczewski K, Hofmann KP. Activation of rhodopsin: new insights from structural and biochemical studies. Trends Biochem Sci 2001; 26: 318-324.
24. Elling CE, Frimurer TM, Gerlach LO, Jorgensen R, Holst B, Schwartz TW. Metal ion site engineering indicates a global toggle switch model for seven-transmembrane receptor activation. J Biol Chem 2006; 281: 17337-17346.
25. Schwartz TW, Frimurer TM, Holst B, Rosenkilde MM, Elling CE. Molecular mechanism of 7TM receptor activation--a global toggle switch model. Annu Rev Pharmacol Toxicol 2006; 46: 481-519.
26. Gouldson PR, Kidley NJ, Bywater RP, Psaroudakis G, Brooks HD, Diaz C, Shire D, Reynolds CA. Toward the active conformations of rhodopsin and the beta2-adrenergic receptor. Proteins 2004; 56: 67-84.
27. Niv MY, Skrabanek L, Filizola M, Weinstein H. Modeling activated states of GPCRs: the rhodopsin template. J Comput Aided Mol Des 2006; 20: 437-448.
28. Tikhonova IG, Best RB, Engel S, Gershengorn MC, Hummer G, Costanzi S. Atomistic insights into rhodopsin activation from a dynamic model. J Am Chem Soc 2008; 130: 10141-10149.
29. Fanelli F, De Benedetti PG. Inactive and active states and supramolecular organization of GPCRs: insights from computational modeling. J Comput Aided Mol Des 2006; 20: 449-461.
30. Bhattacharya S, Vaidehi N. Computational Mapping of the Conformational Transitions in Agonist Selective Pathways of a G-Protein Coupled Receptor. J Amer Chem Soc 2010; 132: 5205-5214.
31. Li Y, Zhu F, Vaidehi N, Goddard WA, III, Sheinerman F, Reiling S, Morize I, Mu L, Harris K, Ardati A, Laoui A. Prediction of the 3D structure and dynamics of human DP G-protein coupled receptor bound to an agonist and an antagonist. J Am Chem Soc 2007; 129: 10720-10731.
32. Floquet N, M'Kadmi C, Perahia D, Gagne D, Berge G, Marie J, Baneres JL, Galleyrand JC, Fehrentz JA, Martinez J. Activation of the ghrelin receptor is described by a privileged collective motion: a model for constitutive and agonist-induced activation of a sub-class A G-protein coupled receptor (GPCR). J Mol Biol 2010; 395: 769-784.
33. Periole X, Huber T, Marrink SJ, Sakmar TP. G protein-coupled receptors self-assemble in dynamics simulations of model bilayers. J Am Chem Soc 2007; 129: 10126-10132.
34. Eswar N, Webb B, Marti-Renom MA, Madhusudham MS, Eramian D, Shen M, Pieper U, Sali A. Comparative Protein Structure Modeling With MODELLER. Current Protocols in Bioinformatics 2006; 15: 5.6.1-5.6.30.
35. Marti-Renom MA, Stuart AC, Fiser A, Sanchez R, Melo F, Sali A. Comparative protein structure modeling of genes and genomes. Annu Rev Biophys Biomol Struct 2000; 29: 291-325.
36. Dunbrack RL, Jr., Karplus M. Backbone-dependent rotamer library for proteins. Application to side-chain prediction. J Mol Biol 1993; 230: 543-574.
37. Im W, Feig M, Brooks CL, III. An implicit membrane generalized born theory for the study of structure, stability, and interactions of membrane proteins. Biophys J 2003; 85: 2900-2918.
38. Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, Karplus M. Charmm - A Program for Macromolecular Energy, Minimization, and Dynamics Calculations. J Comput Chem 1983; 4: 187-217.
39. Tesmer JJ, Sunahara RK, Gilman AG, Sprang SR. Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha.GTPgammaS. Science 1997; 278: 1907-1916.
40. Lambright DG, Sondek J, Bohm A, Skiba NP, Hamm HE, Sigler PB. The 2.0 A crystal structure of a heterotrimeric G protein. Nature 1996; 379: 311-319.
41. Wall MA, Coleman DE, Lee E, Iniguez-Lluhi JA, Posner BA, Gilman AG, Sprang SR. The structure of the G protein heterotrimer Gi alpha 1 beta 1 gamma 2. Cell 1995; 83: 1047-1058.
42. Altenbach C, Cai K, Klein-Seetharaman J, Khorana HG, Hubbell WL. Structure and function in rhodopsin: mapping light-dependent changes in distance between residue 65 in helix TM1 and residues in the sequence 306-319 at the cytoplasmic end of helix TM7 and in helix H8. Biochemistry 2001; 40: 15483-15492.
43. Altenbach C, Klein-Seetharaman J, Cai K, Khorana HG, Hubbell WL. Structure and function in rhodopsin: mapping light-dependent changes in distance between residue 316 in helix 8 and residues in the sequence 60-75, covering the cytoplasmic end of helices TM1 and TM2 and their connection loop CL1. Biochemistry 2001; 40: 15493-15500.
44. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery JrJA, Vreven T, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox D, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA. Gaussian 03, Rev C.02, Gaussian Inc, Wallingford CT 2004.
45. Okada T, Sugihara M, Bondar AN, Elstner M, Entel P, Buss V. The retinal conformation and its environment in rhodopsin in light of a new 2.2 A crystal structure. J Mol Biol 2004; 342: 571-583.
46. Ballesteros JA, Weinstein H. Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G-protein coupled receptors. Methods Neurosci 1995; 25: 366-428.
47. Elling CE, Thirstrup K, Holst B, Schwartz TW. Conversion of agonist site to metal-ion chelator site in the beta(2)-adrenergic receptor. Proc Natl Acad Sci U S A 1999; 96: 12322-12327.
48. Zeng FY, Hopp A, Soldner A, Wess J. Use of a disulfide cross-linking strategy to study muscarinic receptor structure and mechanisms of activation. J Biol Chem 1999; 274: 16629-16640.
49. Wess J, Han SJ, Kim SK, Jacobson KA, Li JH. Conformational changes involved in G-protein-coupled-receptor activation. Trends Pharmacol Sci 2008; 29: 616-625.
50. Ward SD, Hamdan FF, Bloodworth LM, Wess J. Conformational changes that occur during M3 muscarinic acetylcholine receptor activation probed by the use of an in situ disulfide cross-linking strategy. J Biol Chem 2002; 277: 2247-2257.
51. Ward SD, Hamdan FF, Bloodworth LM, Siddiqui NA, Li JH, Wess J. Use of an in situ disulfide cross-linking strategy to study the dynamic properties of the cytoplasmic end of transmembrane domain VI of the M3 muscarinic acetylcholine receptor. Biochemistry 2006; 45: 676-685.
52. Li JH, Han SJ, Hamdan FF, Kim SK, Jacobson KA, Bloodworth LM, Zhang X, Wess J. Distinct structural changes in a G protein-coupled receptor caused by different classes of agonist ligands. J Biol Chem 2007; 282: 26284-26293.
53. Li JH, Hamdan FF, Kim SK, Jacobson KA, Zhang X, Han SJ, Wess J. Ligand-specific changes in M3 muscarinic acetylcholine receptor structure detected by a disulfide scanning strategy. Biochemistry 2008; 47: 2776-2788.
54. Han SJ, Hamdan FF, Kim SK, Jacobson KA, Bloodworth LM, Li B, Wess J. Identification of an agonist-induced conformational change occurring adjacent to the ligand-binding pocket of the M(3) muscarinic acetylcholine receptor. J Biol Chem 2005; 280: 34849-34858.
55. Hamdan FF, Ward SD, Siddiqui NA, Bloodworth LM, Wess J. Use of an in situ disulfide cross-linking strategy to map proximities between amino acid residues in transmembrane domains I and VII of the M3 muscarinic acetylcholine receptor. Biochemistry 2002; 41: 7647-7658.
56. Han SJ, Hamdan FF, Kim SK, Jacobson KA, Brichta L, Bloodworth LM, Li JH, Wess J. Pronounced conformational changes following agonist activation of the M(3) muscarinic acetylcholine receptor. J Biol Chem 2005; 280: 24870-24879.
57. Nygaard R, Frimurer TM, Holst B, Rosenkilde MM, Schwartz TW. Ligand binding and micro-switches in 7TM receptor structures. Trends Pharmacol Sci 2009; 30: 249-259.
58. Chabre M, Breton J. Orientation of aromatic residues in rhodopsin. Rotation of one tryptophan upon the meta I to meta II transition after illumination. Photochem Photobiol 1979; 30: 295-299.
59. Crocker E, Eilers M, Ahuja S, Hornak V, Hirshfeld A, Sheves M, Smith SO. Location of Trp265 in metarhodopsin II: implications for the activation mechanism of the visual receptor rhodopsin. J Mol Biol 2006; 357: 163-172.
60. Lin SW, Sakmar TP. Specific tryptophan UV-absorbance changes are probes of the transition of rhodopsin to its active state. Biochemistry 1996; 35: 11149-11159.
61. Patel AB, Crocker E, Reeves PJ, Getmanova EV, Eilers M, Khorana HG, Smith SO. Changes in interhelical hydrogen bonding upon rhodopsin activation. J Mol Biol 2005; 347: 803-812.
62. Rafferty CN, Muellenberg CG, Shichi H. Tryptophan in bovine rhodopsin: its content, spectral properties and environment. Biochemistry 1980; 19: 2145-2151.
63. Ruprecht JJ, Mielke T, Vogel R, Villa C, Schertler GF. Electron crystallography reveals the structure of metarhodopsin I. EMBO J 2004; 23: 3609-3620.
64. Shi L, Liapakis G, Xu R, Guarnieri F, Ballesteros JA, Javitch JA. Beta2 adrenergic receptor activation. Modulation of the proline kink in transmembrane 6 by a rotamer toggle switch. J Biol Chem 2002; 277: 40989-40996.
65. Visiers I, Ballesteros JA, Weinstein H. Three-dimensional representations of G protein-coupled receptor structures and mechanisms. Methods Enzymol 2002; 343: 329-371.
66. Liapakis G, Ballesteros JA, Papachristou S, Chan WC, Chen X, Javitch JA. The forgotten serine. A critical role for Ser-2035.42 in ligand binding to and activation of the beta 2-adrenergic receptor. J Biol Chem 2000; 275: 37779-37788.
67. Sato T, Kobayashi H, Nagao T, Kurose H. Ser203 as well as Ser204 and Ser207 in fifth transmembrane domain of the human beta2-adrenoceptor contributes to agonist binding and receptor activation. Br J Pharmacol 1999; 128: 272-274.
68. Gouldson PR, Winn PJ, Reynolds CA. A molecular dynamics approach to receptor mapping: application to the 5HT3 and beta 2-adrenergic receptors. J Med Chem 1995; 38: 4080-4086.
69. Wieland K, Zuurmond HM, Krasel C, IJzerman AP, Lohse MJ. Involvement of Asn-293 in stereospecific agonist recognition and in activation of the beta 2-adrenergic receptor. Proc Natl Acad Sci U S A 1996; 93: 9276-9281.
70. Li X, Hassan SA, Mehler EL. Long dynamics simulations of proteins using atomistic force fields and a continuum representation of solvent effects: calculation of structural and dynamic properties. Proteins 2005; 60: 464-484.
71. Bastug T, Kuyucak S. Importance of the peptide backbone description in modeling the selectivity filter in potassium channels. Biophys J 2009; 96: 4006-4012.
72. Buck M, Bouguet-Bonnet S, Pastor RW, Mackerell AD, Jr. Importance of the CMAP correction to the CHARMM22 protein force field: dynamics of hen lysozyme. Biophys J 2006; 90: L36-L38.
73. Zhang M, Tao YX, Ryan GL, Feng X, Fanelli F, Segaloff DL. Intrinsic differences in the response of the human lutropin receptor versus the human follitropin receptor to activating mutations. J Biol Chem 2007; 282: 25527-25539.
74. Feng X, Muller T, Mizrachi D, Fanelli F, Segaloff DL. An intracellular loop (IL2) residue confers different basal constitutive activities to the human lutropin receptor and human thyrotropin receptor through structural communication between IL2 and helix 6, via helix 3. Endocrinology 2008; 149: 1705-1717.
75. Raimondi F, Seeber M, Benedetti PG, Fanelli F. Mechanisms of inter- and intramolecular communication in GPCRs and G proteins. J Am Chem Soc 2008; 130: 4310-4325.
76. Hurst DP, Grossfield A, Lynch DL, Feller S, Romo TD, Gawrisch K, Pitman MC, Reggio PH. A Lipid Pathway for Ligand Binding Is Necessary for a Cannabinoid G Protein-coupled Receptor. J Biol Chem 2010; 285: 17954-17964.
77. Romo TD, Grossfield A, Pitman MC. Concerted interconversion between ionic lock substates of the beta(2) adrenergic receptor revealed by microsecond timescale molecular dynamics. Biophys J 2010; 98: 76-84.
78. Grossfield A, Pitman MC, Feller SE, Soubias O, Gawrisch K. Internal hydration increases during activation of the G-protein-coupled receptor rhodopsin. J Mol Biol 2008; 381: 478-486.
79. Jardon-Valadez E, Bondar AN, Tobias DJ. Coupling of Retinal, Protein, and Water Dynamics in Squid Rhodopsin. Biophys J 2010; 99: 2200-2207.
80. Jardon-Valadez E, Bondar AN, Tobias DJ. Dynamics of the Internal Water Molecules in Squid Rhodopsin. Biophys J 2009; 96: 2572-2576.
81. Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph 1996; 14: 33-38.
82. Dewar MJS, Zoebisch EG, Healy EF, Stewart JJP. Am1 - A New General-Purpose Quantum-Mechanical Molecular-Model (Vol 107, Pg 3902, 1985). J Am Chem Soc 1993; 115: 5348.
83. Binkley JS, Pople JA, Hehre WJ. Self-Consistent Molecular-Orbital Methods 21. Small Split-Valence Basis-Sets for 1St-Row Elements. J Am Chem Soc 1980; 102: 939-947.
84. Totrov M, Abagyan R. Flexible ligand docking to multiple receptor conformations: a practical alternative. Curr Opin Struct Biol 2008; 18: 178-184.
85. Novoa EM, de Pouplana LR, Barril X, Orozco M. Ensemble Docking from Homology Models. J Chem Theory Comput 2010; 6: 2547-2557.
86. Fulle S, Christ NA, Kestner E, Gohlke H. HIV-1 TAR RNA spontaneously undergoes relevant apo-to-holo conformational transitions in molecular dynamics and constrained geometrical simulations. J Chem Inf Model 2010; 50: 1489-1501.
87. Barril X, Morley SD. Unveiling the full potential of flexible receptor docking using multiple crystallographic structures. J Med Chem 2005; 48: 4432-4443.
88. Ligprep, version 2.2207, Schrodinger, LLC, New York, NY. 2008.
89. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 2004; 47: 1739-1749.
90. Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem 2004; 47: 1750-1759.
91. Meyer T, Ferrer-Costa C, Perez A, Rueda M, Bidon-Chanal A, Luque FJ, Laughton CA, Orozco M. Essential dynamics: a tool for efficient trajectory compression and management. J Chem Theory Comput 2006; 2: 251-258.
92. Grant BJ, Rodrigues AP, ElSawy KM, McCammon JA, Caves LS. Bio3d: an R package for the comparative analysis of protein structures. Bioinformatics 2006; 22: 2695-2696.
93. Ihaka R, Gentleman R. R: A language for data analysis and graphics. J Comput Graph Statistics 1996; 5: 299-314.
94. Maggio R, Vogel Z, Wess J. Coexpression studies with mutant muscarinic/adrenergic receptors provide evidence for intermolecular "cross-talk" between G-protein- linked receptors. Proc Natl Acad Sci U S A 1993; 90: 3103-3107.
95. Bakker RA, Dees G, Carrillo JJ, Booth RG, Lopez-Gimenez JF, Milligan G, Strange PG, Leurs R. Domain swapping in the human histamine H1 receptor. J Pharmacol Exp Ther 2004; 311: 131-138.
96. Dean MK, Higgs C, Smith RE, Bywater RP, Snell CR, Scott PD, Upton GJ, Howe TJ, Reynolds CA. Dimerization of G-protein-coupled receptors. J Med Chem 2001; 44: 4595-4614.
97. Barak LS, Tiberi M, Freedman NJ, Kwatra MM, Lefkowitz RJ, Caron MG. A highly conserved tyrosine residue in G protein-coupled receptors is required for agonist-mediated beta 2-adrenergic receptor sequestration. J Biol Chem 1994; 269: 2790-2795.
98. Barak LS, Menard L, Ferguson SS, Colapietro AM, Caron MG. The conserved seven-transmembrane sequence NP(X)2, 3Y of the G-protein-coupled receptor superfamily regulates multiple properties of the beta 2-adrenergic receptor. Biochemistry 1995; 34: 15407-15414.
99. Dixon RA, Sigal IS, Strader CD. Structure-function analysis of the beta-adrenergic receptor. Cold Spring Harb Symp Quant Biol 1988;53 Pt 1: 487-497.
100. Gabilondo AM, Krasel C, Lohse MJ. Mutations of Tyr326 in the beta 2-adrenoceptor disrupt multiple receptor functions. Eur J Pharmacol 1996; 307: 243-250.
101. Bokoch MP, Zou Y, Rasmussen SG, Liu CW, Nygaard R, Rosenbaum DM, Fung JJ, Choi HJ, Thian FS, Kobilka TS, Puglisi JD, Weis WI, Pardo L, Prosser RS, Mueller L, Kobilka BK. Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor. Nature 2010; 463: 108-112.
102. Ahuja S, Hornak V, Yan EC, Syrett N, Goncalves JA, Hirshfeld A, Ziliox M, Sakmar TP, Sheves M, Reeves PJ, Smith SO, Eilers M. Helix movement is coupled to displacement of the second extracellular loop in rhodopsin activation. Nat Struct Mol Biol 2009; 16: 168-175.
103. Prioleau C, Visiers I, Ebersole BJ, Weinstein H, Sealfon SC. Conserved helix 7 tyrosine acts as a multistate conformational switch in the 5HT2C receptor. J Biol Chem 2002; 277: 36577.
104. Strader CD, Candelore MR, Hill WS, Sigal IS, Dixon RA. Identification of two serine residues involved in agonist activation of the beta-adrenergic receptor. J Biol Chem 1989; 264: 13572-13578.
105. Ballesteros JA, Jensen AD, Liapakis G, Rasmussen SG, Shi L, Gether U, Javitch JA. Activation of the beta 2-adrenergic receptor involves disruption of an ionic lock between the cytoplasmic ends of transmembrane segments 3 and 6. J Biol Chem 2001; 276: 29171-29177.
106. Hanson MA, Cherezov V, Griffith MT, Roth CB, Jaakola VP, Chien EY, Velasquez J, Kuhn P, Stevens RC. A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor. Structure 2008; 16: 897-905.
107. Strader CD, Sigal IS, Candelore MR, Rands E, Hill WS, Dixon RA. Conserved aspartic acid residues 79 and 113 of the beta-adrenergic receptor have different roles in receptor function. J Biol Chem 1988; 263: 10267-10271.
108. Dixon RA, Sigal IS, Rands E, Register RB, Candelore MR, Blake AD, Strader CD. Ligand binding to the beta-adrenergic receptor involves its rhodopsin-like core. Nature 1987; 326: 73-77.
109. Hausdorff WP, Hnatowich M, O'Dowd BF, Caron MG, Lefkowitz RJ. A mutation of the beta 2-adrenergic receptor impairs agonist activation of adenylyl cyclase without affecting high affinity agonist binding. Distinct molecular determinants of the receptor are involved in physical coupling to and functional activation of Gs. J Biol Chem 1990; 265: 1388-1393.
110. Strader CD, Dixon RA, Cheung AH, Candelore MR, Blake AD, Sigal IS. Mutations that uncouple the beta-adrenergic receptor from Gs and increase agonist affinity. J Biol Chem 1987; 262: 16439-16443.
111. Spalding TA, Birdsall NJ, Curtis CA, Hulme EC. Acetylcholine mustard labels the binding site aspartate in muscarinic acetylcholine receptors. J Biol Chem 1994; 269: 4092-4097.
112. Horn F, Weare J, Beukers MW, Horsch S, Bairoch A, Chen W, Edvardsen O, Campagne F, Vriend G. GPCRDB: an information system for G protein-coupled receptors. Nucleic Acids Res 1998; 26: 275-279.
113. Strader CD, Candelore MR, Hill WS, Dixon RA, Sigal IS. A single amino acid substitution in the beta-adrenergic receptor promotes partial agonist activity from antagonists. J Biol Chem 1989; 264: 16470-16477.
114. Cho W, Taylor LP, Mansour A, Akil H. Hydrophobic residues of the D2 dopamine receptor are important for binding and signal transduction. J Neurochem 1995; 65: 2105-2115.
115. Strader CD, Fong TM, Tota MR, Underwood D, Dixon RA. Structure and function of G protein-coupled receptors. Annu Rev Biochem 1994; 63: 101-132.
116. Javitch JA, Ballesteros JA, Weinstein H, Chen J. A cluster of aromatic residues in the sixth membrane-spanning segment of the dopamine D2 receptor is accessible in the binding-site crevice. Biochemistry 1998; 37: 998-1006.
117. Warren GL, Andrews CW, Capelli AM, Clarke B, LaLonde J, Lambert MH, Lindvall M, Nevins N, Semus SF, Senger S, Tedesco G, Wall ID, Woolven JM, Peishoff CE, Head MS. A critical assessment of docking programs and scoring functions. J Med Chem 2006; 49: 5912-5931.
118. Katritch V, Reynolds KA, Cherezov V, Hanson MA, Roth CB, Yeager M, Abagyan R. Analysis of full and partial agonists binding to beta2-adrenergic receptor suggests a role of transmembrane helix V in agonist-specific conformational changes. J Mol Recognit 2009; 22: 307-318.