Browse > Article
http://dx.doi.org/10.5487/TR.2013.29.3.149

Structural Aspects of GPCR-G Protein Coupling  

Chung, Ka Young (School of Pharmacy, Sungkyunkwan University)
Publication Information
Toxicological Research / v.29, no.3, 2013 , pp. 149-155 More about this Journal
Abstract
G protein-coupled receptors (GPCRs) are membrane receptors; approximately 40% of drugs on the market target GPCRs. A precise understanding of the activation mechanism of GPCRs would facilitate the development of more effective and less toxic drugs. Heterotrimeric G proteins are important molecular switches in GPCR-mediated signal transduction. An agonist-activated receptor interacts with specific sites on G proteins and promotes the release of GDP from the $G{\alpha}$ subunit. Because of the important biological role of the GPCR-G protein coupling, conformational changes in the G protein upon receptor coupling have been of great interest. One of the most important questions was the interface between the GPCR and G proteins and the structural mechanism of GPCR-induced G protein activation. A number of biochemical and biophysical studies have been performed since the late 80s to address these questions; there was a significant breakthrough in 2011 when the crystal structure of a GPCR-G protein complex was solved. This review discusses the structural aspects of GPCR-G protein coupling by comparing the results of previous biochemical and biophysical studies to the GPCR-G protein crystal structure.
Keywords
GPCR; G protein; Structure;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Coleman, D.E., Berghuis, A.M., Lee, E., Linder, M.E., Gilman, A.G. and Sprang, S.R. (1994) Structures of active conformations of Gi alpha 1 and the mechanism of GTP hydrolysis. Science, 265, 1405-1412.   DOI
2 Venkatakrishnan, A.J., Deupi, X., Lebon, G., Tate, C.G., Schertler, G.F. and Babu, M.M. (2013) Molecular signatures of G-protein-coupled receptors. Nature, 494, 185-194.   DOI   ScienceOn
3 Rasmussen, S.G., DeVree, B.T., Zou, Y., Kruse, A.C., Chung, K.Y., Kobilka, T.S., Thian, F.S., Chae, P.S., Pardon, E., Calinski, D., Mathiesen, J.M., Shah, S.T., Lyons, J.A., Caffrey, M., Gellman, S.H., Steyaert, J., Skiniotis, G., Weis, W.I., Sunahara, R.K. and Kobilka, B.K. (2011) Grystal structure of the $\beta2$ adrenergic receptor-Gs protein complex. Nature, 477, 549-555.   DOI   ScienceOn
4 Preininger, A.M., Van Eps, N., Yu, N.J., Medkova, M., Hubbell, W.L. and Hamm, H.E. (2003) The myristoylated amino terminus of Galpha(i)(1) plays a critical role in the structure and function of Galpha(i)(1) subunits in solution. Biochemistry, 42, 7931-7941.   DOI   ScienceOn
5 Franco, M., Chardin, P., Chabre, M. and Paris, S. (1996) Myristoylation-facilitated binding of the G protein ARF1GDP to membrane phospholipids is required for its activation by a soluble nucleotide exchange factor. J. Biol. Chem., 271, 1573-1578.   DOI
6 Degtyarev, M.Y., Spiegel, A.M. and Jones, T.L. (1994) Palmitoylation of a G protein alpha i subunit requires membrane localization not myristoylation. J. Biol. Chem., 269, 30898-30903.
7 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 alpha subunit. Science, 241, 832-835.   DOI
8 Wang, X., Kim, S.H., Ablonczy, Z., Crouch, R.K. and Knapp, D.R. (2004) Probing rhodopsin-transducin interactions by surface modification and mass spectrometry. Biochemistry, 43, 11153-11162.   DOI   ScienceOn
9 Oldham, W.M. and Hamm, H.E. (2008) Heterotrimeric G protein activation by G-protein-coupled receptors. Nat. Rev. Mol. Cell Biol., 9, 60-71.   DOI   ScienceOn
10 Baltoumas, F.A., Theodoropoulou, M.C. and Hamodrakas, S.J. (2013) Interactions of the α-subunits of heterotrimeric Gproteins with GPCRs, effectors and RGS proteins: a critical review and analysis of interacting surfaces, conformational shifts, structural diversity and electrostatic potentials. J. Struct. Biol., 182, 209-218.   DOI   ScienceOn
11 Tesmer, J.J. (2010) The quest to understand heterotrimeric G protein signaling. Nat. Struct. Mol. Biol., 17, 650-652.   DOI   ScienceOn
12 Jones, J.C., Duffy, J.W., Machius, M., Temple, B.R., Dohlman, H.G. and Jones, A.M. (2011) The crystal structure of a self-activating G protein alpha subunit reveals its distinct mechanism of signal initiation. Sci. Signaling, 4, ra8.   DOI   ScienceOn
13 Lambright, D.G., Sondek, J., Bohm, A., Skiba, N.P., Hamm, H.E. and Sigler, P.B. (1996) The 2.0A crystal structure of a heterotrimeric G protein. Nature, 379, 311-319.   DOI   ScienceOn
14 Sondek, J., Bohm, A., Lambright, D.G., Hamm, H.E. and Sigler, P.B. (1996) Crystal structure of a G-protein beta gamma dimer at 2.1A resolution. Nature, 379, 369-374.   DOI   ScienceOn
15 Wall, M.A., Coleman, D.E., Lee, E., Iiguez-Lluhi, J.A., Posner, B.A., Gilman, A.G. and Sprang, S.R. (1995) The structure of the G protein heterotrimer Gi alpha 1 beta 1 gamma 2. Cell, 83, 1047-1058.   DOI   ScienceOn
16 Lambright, D.G., Noel, J.P., Hamm, H.E. and Sigler, P.B. (1994) Structural determinants for activation of the alpha-subunit of a heterotrimeric G protein. Nature, 369, 621-628.   DOI   ScienceOn
17 Nikiforovich, G.V., Taylor, C.M. and Marshall, G.R. (2007) Modeling of the complex between transducin and photoactivated rhodopsin, a prototypical G-protein-coupled receptor. Biochemistry, 46, 4734-4744.   DOI   ScienceOn
18 Sondek, J., Lambright, D.G., Noel, J.P., Hamm, H.E. and Sigler, P.B. (1994) GTPase mechanism of Gproteins from the 1.7-A crystal structure of transducin alpha-GDP-AIF-4. Nature, 372, 276-279.   DOI   ScienceOn
19 Noel, J.P., Hamm, H.E. and Sigler, P.B. (1993) The 2.2A crystal structure of transducin-alpha complexed with GTP gamma S. Nature, 366, 654-663.   DOI   ScienceOn
20 Lundstrom, K. (2009) An overview on GPCRs and drug discovery: structure-based drug design and structural biology on GPCRs. Methods Mol Biol., 552, 51-66.   DOI   ScienceOn
21 Sunahara, R.K., Tesmer, J.J., Gilman, A.G. and Sprang, S.R. (1997) Crystal structure of the adenylyl cyclase activator Gsalpha. Science, 278, 1943-1947.   DOI   ScienceOn
22 Mixon, M.B., Lee, E., Coleman, D.E., Berghuis, A.M., Gilman, A.G. and Sprang, S.R. (1995) Tertiary and quaternary structural changes in Gi alpha 1 induced by GTP hydrolysis. Science, 270, 954-960.   DOI   ScienceOn
23 Gales, C., Van Durm, J.J., Schaak, S., Pontier, S., Percherancier, Y., Audet, M., Paris, H. and Bouvier, M. (2006) Probing the activation-promoted structural rearrangements in preassembled receptor-G protein complexes. Nat. Struct. Mol. Biol., 13, 778-786.   DOI   ScienceOn
24 Challiss, R.A. and Wess, J. (2011) Receptors: GPCR-G protein preassembly? Nat. Chem. Biol., 7, 657-658.   DOI   ScienceOn
25 Marin, E.P., Krishna, A.G. and Sakmar, T.P. (2002) Disruption of the alpha5 helix of transducin impairs rhodopsin-catalyzed nucleotide exchange. Biochemistry, 41, 6988-6994.   DOI   ScienceOn
26 Cherfils, J. and Chabre, M. (2003) Activation of G-protein Galpha subunits by receptors through Galpha-Gbeta and Galpha-Ggamma interactions. Trends Biochem. Sci., 28, 13-17.   DOI   ScienceOn
27 Kapoor, N., Menon, S.T., Chauhan, R., Sachdev, P. and Sakmar, T.P. (2009) Structural evidence for a sequential release mechanism for activation of heterotrimeric G proteins. J. Mol. Biol., 393, 882-897.   DOI   ScienceOn
28 Preininger, A.M., Parello, J., Meier, S.M., Liao, G. and Hamm, H.E. (2008) Receptor-mediated changes at the myristoylated amino terminus of Galpha(il) proteins. Biochemistry, 47, 10281-10293.   DOI   ScienceOn
29 Kisselev, O.G. and Downs, M.A. (2003) Rhodopsin controls a conformational switch on the transducin gamma subunit. Structure, 11, 367-373.   DOI   ScienceOn
30 Rondard, P., Iiri, T., Srinivasan, S., Meng, E., Fujita, T. and Bourne, H.R. (2001) Mutant G protein alpha subunit activated by Gbeta gamma: a model for receptor activation? Proc. Natl. Acad. Sci. U. S. A., 98, 6150-6155.   DOI   ScienceOn
31 Patowary, S., Alvarez-Curto, E., Xu, T.R., Holz, J.D., Oliver, J.A., Milligan, G. and Raicu, V. (2013) The muscarinic M3 acetylcholine receptor exists as two differently sized complexes at the plasma membrane. Biochem. J., 452, 303-312.   DOI   ScienceOn
32 Watts, A.O., van Lipzig, M.M., Jaeger, W.C., Seeber, R.M., van Zwam, M., Vinet, J., van der Lee, M.M., Siderius, M., Zaman, G.J., Boddeke, H.W., Smit, M.J., Pfleger, K.D., Leurs, R. and Vischer, H.F. (2013) Identification and profiling of CXCR3-CXCR4 chemokine receptor heteromer complexes. Br. J. Pharmacol., 168, 1662-1674.   DOI   ScienceOn
33 Teitler, M. and Klein, M.T. (2012) A new approach for studying GPCR dimers: drug-induced inactivation and reactivation to reveal GPCR dimer function in vitro, in primary culture, and in vivo. Pharmacol. Ther., 133, 205-217.   DOI   ScienceOn
34 Natochin, M., Moussaif, M. and Artemyev, N.O. (2001) Probing the mechanism of rhodopsin-catalyzed transducin activation. J. Neurochem., 77, 202-210.   DOI
35 Ayoub, M.A., Al-Senaidy, A. and Pin, J.P. (2012) Receptor-G protein interaction studied by bioluminescence resonance energy transfer: lessons from protease-activated receptor 1. Front. Endocrinol. (Lausanne), 3, 82.
36 Qin, K., Dong, C., Wu, G. and Lambert, N.A. (2011) Inactivestate preassembly of G(q)-coupled receptors and G(q) heterotrimers. Nat. Chem. Biol., 7, 740-747.   DOI   ScienceOn
37 Qin, K., Sethi, P.R. and Lambert, N.A. (2008) Abundance and stability of complexes containing inactive G protein-coupled receptors and G proteins. FASEB J., 22, 2920-2927.   DOI   ScienceOn
38 Marin, E.P., Krishna, A.G. and Sakmar, T.P. (2001) Rapid activation of transducin by mutations distant from the nucleotidebinding site: evidence for a mechanistic model of receptor-catalyzed nucleotide exchange by G proteins. J. Biol. Chem., 276, 27400-27405.   DOI   ScienceOn
39 Grishina, G. and Berlot, C.H. (2000) A surface-exposed region of G(salpha) in which substitutions decrease receptor-mediated activation and increase receptor affinity. Mol. Pharmacol., 57, 1081-1092.
40 Yu, M.Y., Ho, M.K., Liu, A.M. and Wong, Y.H. (2008) Mutations on the Switch III region and the alpha3 helix of Galpha16 differentially affect receptor coupling and regulation of downstream effectors. J. Mol. Signaling, 3, 17.   DOI   ScienceOn
41 Westfield, G.H., Rasmussen, S.G., Su, M., Dutta, S., DeVree, B.T., Chung, K.Y., Calinski, D., Velez-Ruiz, G., Oleskie, A.N., Pardon, E., Chae, P.S., Liu, T., Li, S., Woods, V.L. Jr., Steyaert, J., Kobilka, B.K., Sunahara, R.K. and Skiniotis, G. (2011) Structural flexibility of the G alpha s alpha-helical domain in the beta2-adrenoceptor Gs complex. Proc. Natl. Acad. Sci. U. S. A., 108, 16086-16091.   DOI   ScienceOn
42 Kisselev, O.G., Kao, J., Ponder, J.W., Fann, Y.C., Gautam, N. and Marshall, G.R. (1998) Light-activated rhodopsin induces structural binding motif in G protein alpha subunit. Proc. Natl. Acad. Sci. U. S. A., 95, 4270-4275.   DOI   ScienceOn
43 Abdulaev, N.G., Ngo, T., Ramon, E., Brabazon, D.M., Marino, J.P. and Ridge, K.D. (2006) The receptor-bound “empty pocket” state of the heterotrimeric G-protein alpha-subunit is conformationally dynamic. Biochemistry, 45, 12986-12997.   DOI   ScienceOn
44 Van Eps, N., Preininger, A.M., Alexander, N., Kaya, A.I., Meier, S., Meiler, J., Hamm, H.E. and Hubbell, W.L. (2011) Interaction of a G protein with an activated receptor opens the interdomain interface in the alpha subunit. Proc. Natl. Acad. Sci. U. S. A., 108, 9420-9424.   DOI   ScienceOn
45 Dratz, E.A., Furstenau, J.E., Lambert, C.G., Thireault, D.L., Rarick, H., Schepers, T., Pakhlevaniants, S. and Hamm, H.E. (1993) NMR structure of a receptor-bound G-protein peptide. Nature, 363, 276-281.   DOI   ScienceOn
46 Koenig, B.W., Kontaxis, G., Mitchell, D.C., Louis, J.M., Litman, B.J. and Bax, A. (2002) Structure and orientation of a G protein fragment in the receptor bound state from residual dipolar couplings. J. Mol. Biol., 322, 441-461.   DOI   ScienceOn
47 Brabazon, D.M., Abdulaev, N.G., Marino, J.P. and Ridge, K.D. (2003) Evidence for structural changes in carboxyl-terminal peptides of transducin alpha-subunit upon binding a soluble mimic of light-activated rhodopsin. Biochemistry, 42, 302-311.   DOI   ScienceOn
48 Oldham, W.M., Van Eps, N., Preininger, A.M., Hubbell, W.L. and Hamm, H.E. (2006) Mechanism of the receptor-catalyzed activation of heterotrimeric G proteins. Nat. Struct. Mol. Biol., 13, 772-777.   DOI   ScienceOn
49 Orban, T., Jastrzebska, B., Gupta, S., Wang, B., Miyagi, M., Chance, M.R. and Palczewski, K. (2012) Conformational dynamics of activation for the pentameric complex of dimeric G protein-coupled receptor and heterotrimeric G protein. Structure, 20, 826-840.   DOI   ScienceOn
50 Chung, K.Y., Rasmussen, S.G., Liu, T., Li, S., DeVree, B.T., Chae, P.S., Calinski, D., Kobilka, B.K., Woods, V.L. Jr. and Sunahara, R.K. (2011) Conformational changes in the G protein Gs induced by the $\beta2$ adrenergic receptor. Nature, 477, 611-615.   DOI   ScienceOn
51 Feldman, D.S., Zamah, A.M., Pierce, K.L., Miller, W.E., Kelly, F., Rapacciuolo, A., Rockman, H.A., Koch, W.J. and Luttrell, L.M. (2002) Selective inhibition of heterotrimeric Gs signaling. Targeting the receptor-G protein interface using a peptide minigene encoding the Galpha(s) carboxyl terminus. J. Biol. Chem., 277, 28631-28640.   DOI   ScienceOn
52 Aris, L., Gilchrist, A., Rens-Domiano, S., Meyer, C., Schatz, P.J., Dratz, E.A. and Hamm, H.E. (2001) Structural requirements for the stabilization of metarhodopsin II by the C terminus of the alpha subunit of transducin. J. Biol. Chem., 276, 2333-2339.   DOI   ScienceOn
53 Schwindinger, W.F., Miric, A., Zimmerman, D. and Levine, M.A. (1994) A novel Gs alpha mutant in a patient with Albright hereditary osteodystrophy uncouples cell surface receptors from adenylyl cyclase. J. Biol. Chem., 269, 25387-25391.
54 Natochin, M., Muradov, K.G., McEntaffer, R.L. and Artemyev, N.O. (2000) Rhodopsin recognition by mutant G(s)alpha containing C-terminal residues of transducin. J. Biol. Chem., 275, 2669-2675.   DOI   ScienceOn
55 Hu, J., Wang, Y., Zhang, X., Lloyd, J.R., Li, J.H., Karpiak, J., Costanzi, S. and Wess, J. (2010) Structural basis of G proteincoupled receptor-G protein interactions. Nat. Chem. Biol., 6, 541-548.   DOI   ScienceOn
56 Cai, K., Itoh, Y. and Khorana, H.G. (2001) Mapping of contact sites in complex formation between transducin and lightactivated rhodopsin by covalent crosslinking: use of a photoactivatable reagent. Proc. Natl. Acad. Sci. U. S. A., 98, 4877-4882.   DOI   ScienceOn
57 Scheerer, P., Park, J.H., Hildebrand, P.W., Kim, Y.J., Krauss, N., Choe, H.W., Hofmann, K.P. and Ernst, O.P. (2008) Crystal structure of opsin in its G-protein-interacting conformation. Nature, 455, 497-502.   DOI   ScienceOn
58 Itoh, Y., Cai, K. and Khorana, H.G. (2001) Mapping of contact sites in complex formation between light-activated rhodopsin and transducin by covalent crosslinking: use of a chemically preactivated reagent. Proc. Natl. Acad. Sci. U. S. A., 98, 4883-4887.   DOI   ScienceOn
59 Choe, H.W., Kim, Y.J., Park, J.H., Morizumi, T., Pai, E.F., Krauss, N., Hofmann, K.P., Scheerer, P. and Ernst, O.P. (2011) Crystal structure of metarhodopsin II. Nature, 471, 651-655.   DOI   ScienceOn
60 Taylor, J.M., Jacob-Mosier, G.G., Lawton, R.G., Remmers, A.E. and Neubig, R.R. (1994) Binding of an alpha 2 adrenergic receptor third intracellular loop peptide to G beta and the amino terminus of G alpha. J. Biol. Chem., 269, 27618-27624.
61 Natochin, M., Granovsky, A.E., Muradov, K.G. and Artemyev, N.O. (1999) Roles of the transducin alpha-subunit alpha4-helixlalpha4-beta6 loop in the receptor and effector interactions. J. Biol. Chem., 274, 7865-7869.   DOI   ScienceOn
62 Bae, H., Cabrera-Vera, T.M., Depree, K.M., Graber, S.G. and Hamm, H.E. (1999) Two amino acids within the alpha4 helix of Galphai1 mediate coupling with 5-hydroxytryptamine1B receptors. J. Biol. Chem., 274, 14963-14971.   DOI   ScienceOn
63 Johnston, C.A. and Siderovski, D.P. (2007) Structural basis for nucleotide exchange on G alpha i subunits and receptor coupling specificity. Proc. Natl. Acad. Sci. U. S. A., 104, 2001-2006.   DOI   ScienceOn