Home LiteratureArticle Details
PMID: 19458711 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

The structure and function of G-protein-coupled receptors.

Nature ·Vol. 459 ·No. 7245 ·2009-05-21 ·Pages 356-63

Rosenbaum DM, Rasmussen SG, Kobilka BK

Abstract

G-protein-coupled receptors (GPCRs) mediate most of our physiological responses to hormones, neurotransmitters and environmental stimulants, and so have great potential as therapeutic targets for a broad spectrum of diseases. They are also fascinating molecules from the perspective of membrane-protein structure and biology. Great progress has been made over the past three decades in understanding diverse GPCRs, from pharmacology to functional characterization in vivo. Recent high-resolution structural studies have provided insights into the molecular mechanisms of GPCR activation and constitutive activity.

MeSH Terms
Animals Conserved Sequence Cytoplasm/metabolism Humans Opsins/chemistry,metabolism Protein Conformation Receptors, G-Protein-Coupled/chemistry,metabolism Signal Transduction
Chemicals
Opsins Receptors, G-Protein-Coupled
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Rosenbaum Daniel M
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Palo Alto, California 94305, USA.
Rasmussen Søren G F
Kobilka Brian K
References (69)
69 references, click to expand
  1. A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor.
    J Biol Chem. 1980 Aug 10;255(15):7108-17 PMID: 6248546
  2. Beta(1)-selective agonist (-)-1-(3,4-dimethoxyphenetylamino)-3-(3,4-dihydroxy)-2-propanol [(-)-RO363] differentially interacts with key amino acids responsible for beta(1)-selective binding in resting and active states.
    J Pharmacol Exp Ther. 2002 Apr;301(1):51-8 PMID: 11907156
  3. The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist.
    Science. 2008 Nov 21;322(5905):1211-7 PMID: 18832607
  4. Conserved aspartic acid residues 79 and 113 of the beta-adrenergic receptor have different roles in receptor function.
    J Biol Chem. 1988 Jul 25;263(21):10267-71 PMID: 2899076
  5. Characterisation of an improved two-dimensional p22121 crystal from bovine rhodopsin.
    J Mol Biol. 1998 Oct 9;282(5):991-1003 PMID: 9753549
  6. Functional role of the "ionic lock"--an interhelical hydrogen-bond network in family A heptahelical receptors.
    J Mol Biol. 2008 Jul 18;380(4):648-55 PMID: 18554610
  7. Bicelle crystallization: a new method for crystallizing membrane proteins yields a monomeric bacteriorhodopsin structure.
    J Mol Biol. 2002 Feb 8;316(1):1-6 PMID: 11829498
  8. Conformational complexity of G-protein-coupled receptors.
    Trends Pharmacol Sci. 2007 Aug;28(8):397-406 PMID: 17629961
  9. A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling.
    Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16657-62 PMID: 17925438
  10. Crystal structure of opsin in its G-protein-interacting conformation.
    Nature. 2008 Sep 25;455(7212):497-502 PMID: 18818650
  11. Identification of two serine residues involved in agonist activation of the beta-adrenergic receptor.
    J Biol Chem. 1989 Aug 15;264(23):13572-8 PMID: 2547766
  12. Agonist-induced conformational changes in the G-protein-coupling domain of the beta 2 adrenergic receptor.
    Proc Natl Acad Sci U S A. 2001 May 22;98(11):5997-6002 PMID: 11353823
  13. Mutation of a highly conserved aspartic acid in the beta2 adrenergic receptor: constitutive activation, structural instability, and conformational rearrangement of transmembrane segment 6.
    Mol Pharmacol. 1999 Jul;56(1):175-84 PMID: 10385699
  14. Functionally different agonists induce distinct conformations in the G protein coupling domain of the beta 2 adrenergic receptor.
    J Biol Chem. 2001 Jul 6;276(27):24433-6 PMID: 11320077
  15. A monoclonal antibody for G protein-coupled receptor crystallography.
    Nat Methods. 2007 Nov;4(11):927-9 PMID: 17952087
  16. Structure-based discovery of beta2-adrenergic receptor ligands.
    Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6843-8 PMID: 19342484
  17. beta-arrestin-dependent, G protein-independent ERK1/2 activation by the beta2 adrenergic receptor.
    J Biol Chem. 2006 Jan 13;281(2):1261-73 PMID: 16280323
  18. Beta2 adrenergic receptor activation. Modulation of the proline kink in transmembrane 6 by a rotamer toggle switch.
    J Biol Chem. 2002 Oct 25;277(43):40989-96 PMID: 12167654
  19. Crystal structure of the ligand-free G-protein-coupled receptor opsin.
    Nature. 2008 Jul 10;454(7201):183-7 PMID: 18563085
  20. The role of internal water molecules in the structure and function of the rhodopsin family of G protein-coupled receptors.
    Chembiochem. 2007 Jan 2;8(1):19-24 PMID: 17173267
  21. Caveolae and lipid rafts: G protein-coupled receptor signaling microdomains in cardiac myocytes.
    Ann N Y Acad Sci. 2005 Jun;1047:166-72 PMID: 16093494
  22. Inverse agonist activity of beta-adrenergic antagonists.
    Mol Pharmacol. 1994 Mar;45(3):490-9 PMID: 7908406
  23. Crystallizing membrane proteins for structure determination: use of lipidic mesophases.
    Annu Rev Biophys. 2009;38:29-51 PMID: 19086821
  24. Homology modeling of G-protein-coupled receptors and implications in drug design.
    Curr Med Chem. 2006;13(14):1667-91 PMID: 16787212
  25. Sequential binding of agonists to the beta2 adrenoceptor. Kinetic evidence for intermediate conformational states.
    J Biol Chem. 2004 Jan 2;279(1):686-91 PMID: 14559905
  26. Functional role of internal water molecules in rhodopsin revealed by X-ray crystallography.
    Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):5982-7 PMID: 11972040
  27. Mutagenesis reveals structure-activity parallels between human A2A adenosine receptors and biogenic amine G protein-coupled receptors.
    J Med Chem. 1997 Aug 1;40(16):2588-95 PMID: 9258366
  28. Crystal structure of the human beta2 adrenergic G-protein-coupled receptor.
    Nature. 2007 Nov 15;450(7168):383-7 PMID: 17952055
  29. Beta-arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors.
    Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11406-11 PMID: 13679574
  30. Conformations of the active and inactive states of opsin.
    J Biol Chem. 2001 Oct 19;276(42):38487-93 PMID: 11502747
  31. Rhodopsin structure, dynamics, and activation: a perspective from crystallography, site-directed spin labeling, sulfhydryl reactivity, and disulfide cross-linking.
    Adv Protein Chem. 2003;63:243-90 PMID: 12629973
  32. Helix movement is coupled to displacement of the second extracellular loop in rhodopsin activation.
    Nat Struct Mol Biol. 2009 Feb;16(2):168-75 PMID: 19182802
  33. Crystal structure of a thermally stable rhodopsin mutant.
    J Mol Biol. 2007 Oct 5;372(5):1179-88 PMID: 17825322
  34. Crystal structure of a photoactivated deprotonated intermediate of rhodopsin.
    Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16123-8 PMID: 17060607
  35. Regulation of GPCRs by endocytic membrane trafficking and its potential implications.
    Annu Rev Pharmacol Toxicol. 2008;48:537-68 PMID: 18184106
  36. GPCRDB information system for G protein-coupled receptors.
    Nucleic Acids Res. 2003 Jan 1;31(1):294-7 PMID: 12520006
  37. Recent developments in constitutive receptor activity and inverse agonism, and their potential for GPCR drug discovery.
    Trends Pharmacol Sci. 2006 Feb;27(2):92-6 PMID: 16406086
  38. 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 Dec 1;275(48):37779-88 PMID: 10964911
  39. Crystal structure of rhodopsin: A G protein-coupled receptor.
    Science. 2000 Aug 4;289(5480):739-45 PMID: 10926528
  40. Sequence of late molecular events in the activation of rhodopsin.
    Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20290-5 PMID: 18077356
  41. High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor.
    Science. 2007 Nov 23;318(5854):1258-65 PMID: 17962520
  42. Desensitization of G protein-coupled receptors.
    Recent Prog Horm Res. 1996;51:319-51; discussion 352-3 PMID: 8701085
  43. The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2 and beta3 adrenoceptors.
    Br J Pharmacol. 2005 Feb;144(3):317-22 PMID: 15655528
  44. High-resolution distance mapping in rhodopsin reveals the pattern of helix movement due to activation.
    Proc Natl Acad Sci U S A. 2008 May 27;105(21):7439-44 PMID: 18490656
  45. Conformational thermostabilization of the beta1-adrenergic receptor in a detergent-resistant form.
    Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):877-82 PMID: 18192400
  46. Probing the beta2 adrenoceptor binding site with catechol reveals differences in binding and activation by agonists and partial agonists.
    J Biol Chem. 2005 Jun 10;280(23):22165-71 PMID: 15817484
  47. Dark adaptation and the retinoid cycle of vision.
    Prog Retin Eye Res. 2004 May;23(3):307-80 PMID: 15177205
  48. Negative antagonists promote an inactive conformation of the beta 2-adrenergic receptor.
    Mol Pharmacol. 1994 Mar;45(3):390-4 PMID: 7908404
  49. GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function.
    Science. 2007 Nov 23;318(5854):1266-73 PMID: 17962519
  50. A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor.
    Structure. 2008 Jun;16(6):897-905 PMID: 18547522
  51. Mechanism of activation and inactivation of opsin: role of Glu113 and Lys296.
    Biochemistry. 1992 Dec 22;31(50):12592-601 PMID: 1472495
  52. Cloning of the gene and cDNA for mammalian beta-adrenergic receptor and homology with rhodopsin.
    Nature. 1986 May 1-7;321(6065):75-9 PMID: 3010132
  53. Structure of bovine rhodopsin in a trigonal crystal form.
    J Mol Biol. 2004 Nov 5;343(5):1409-38 PMID: 15491621
  54. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders.
    Nat Rev Drug Discov. 2009 Jan;8(1):41-54 PMID: 19116626
  55. Roles of G-protein-coupled receptor dimerization.
    EMBO Rep. 2004 Jan;5(1):30-4 PMID: 14710183
  56. Isotope labeling of mammalian GPCRs in HEK293 cells and characterization of the C-terminus of bovine rhodopsin by high resolution liquid NMR spectroscopy.
    J Biomol NMR. 2008 Jan;40(1):49-53 PMID: 17999150
  57. Requirement of rigid-body motion of transmembrane helices for light activation of rhodopsin.
    Science. 1996 Nov 1;274(5288):768-70 PMID: 8864113
  58. The retinal conformation and its environment in rhodopsin in light of a new 2.2 A crystal structure.
    J Mol Biol. 2004 Sep 10;342(2):571-83 PMID: 15327956
  59. Projection structure of rhodopsin.
    Nature. 1993 Apr 22;362(6422):770-2 PMID: 8469290
  60. X-Ray diffraction analysis of three-dimensional crystals of bovine rhodopsin obtained from mixed micelles.
    J Struct Biol. 2000 May;130(1):73-80 PMID: 10806093
  61. Crystallization of bacteriorhodopsin from bicelle formulations at room temperature.
    Protein Sci. 2005 Mar;14(3):836-40 PMID: 15689517
  62. Structure of a beta1-adrenergic G-protein-coupled receptor.
    Nature. 2008 Jul 24;454(7203):486-91 PMID: 18594507
  63. 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 Nov 28;34(47):15407-14 PMID: 7492540
  64. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints.
    Mol Pharmacol. 2003 Jun;63(6):1256-72 PMID: 12761335
  65. Recent advances in cardiac beta(2)-adrenergic signal transduction.
    Circ Res. 1999 Nov 26;85(11):1092-100 PMID: 10571541
  66. The evasive nature of drug efficacy: implications for drug discovery.
    Trends Pharmacol Sci. 2007 Aug;28(8):423-30 PMID: 17659355
  67. Adrenergic receptors in the heart.
    Annu Rev Physiol. 1982;44:475-84 PMID: 6280590
  68. Coupling ligand structure to specific conformational switches in the beta2-adrenoceptor.
    Nat Chem Biol. 2006 Aug;2(8):417-22 PMID: 16799554
  69. 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 Aug 3;276(31):29171-7 PMID: 11375997
Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature08144
Published
2009-05-21
Pages
356-63
Language
English
Region
England
NLM ID
0410462
PMCID
PMC3967846
Subset
IM
Grants
NIGMS NIH HHS · R01-GM083118 · United States
NIGMS NIH HHS · F32 GM082028 · United States
NIGMS NIH HHS · R01 GM083118 · United States
NINDS NIH HHS · R01-NS28471 · United States
NINDS NIH HHS · R01 NS028471 · United States
External Links
PubMed source DOI: 10.1038/nature08144 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2