Skip to main content
PMC home page
The AAPS Journal logoLink to The AAPS Journal
. 2006 May 12;8(2):E322–E336. doi: 10.1007/BF02854903

Computational methods in drug design: Modeling G protein-coupled receptor monomers, dimers, and oligomers

Patricia H Reggio 1,✉
PMCID: PMC3231557  PMID: 16796383

Abstract

G protein-coupled receptors (GPCRs) are membrane proteins that serve as very important links through which cellular signal transduction mechanisms are activated. Many vital physiological events such as sensory perception, immune defense, cell communication, chemotaxis, and neuro-transmission are mediated by GPCRs. Not surprisingly, GPCRs are major targets for drug development today. Most modeling studies in the GPCR field have focused upon the creation of a model of a single GPCR (ie, a GPCR monomer) based upon the crystal structure of the Class A GPCR, rhodopsin. However, the emerging concept of GPCR dimerization has challenged our notions of the monomeric GPCR as functional unit. Recent work has shown not only that many GPCRs exist as homo- and heterodimers but also that GPCR oligomeric assembly may have important functional roles. This review focuses first on methodology for the creation of monomeric GPCR models. Special emphasis is given to the identification of localized regions where the structure of a GPCR may diverge from that of bovine rhodopsin. The review then focuses on GPCR dimers and oligomers and the bioinformatics methods available for identifying homo- and heterodimer interfaces.

Keywords: GPCR modeling, GPCR dimer, GPCR oligomer

Full Text

The Full Text of this article is available as a PDF (512.4 KB).

References

  • 1.Takeda S, Kadowaki S, Haga T, Takaesu H, Mitaku S. Identification of G protein-coupled receptor genes from the human genome sequence. FEBS Lett. 2002;520:97–101. doi: 10.1016/S0014-5793(02)02775-8. [DOI] [PubMed] [Google Scholar]
  • 2.Kolakowski LF. GCRDb: a G-protein-coupled receptor database. Receptors Channels. 1994;2:1–7. [PubMed] [Google Scholar]
  • 3.Bockaert J, Pin JP. Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J. 1999;18:1723–1729. doi: 10.1093/emboj/18.7.1723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Fredriksson R, Lagerstrom MC, Lundin LG, Schioth HB. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol. 2003;63:1256–1272. doi: 10.1124/mol.63.6.1256. [DOI] [PubMed] [Google Scholar]
  • 5.Eilers M, Hornak V, Smith SO, Konopka JB. Comparison of class A and D G protein-coupled receptors: common features in structure and activation. Biochemistry. 2005;44:8959–8975. doi: 10.1021/bi047316u. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.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. In: Sealfon SC, Conn PM, editors. Methods in Neurosciences. San Diego, CA: Academic Press; 1995. pp. 366–428. [Google Scholar]
  • 7.Palczewski K, Kumasaka T, Hori T, et al. Crystal structure of rhodopsin: a G protein-coupled receptor. Science. 2000;289:739–745. doi: 10.1126/science.289.5480.739. [DOI] [PubMed] [Google Scholar]
  • 8.Li J, Edwards PC, Burghammer M, Villa C, Schertler GF. Structure of bovine rhodopsin in a trigonal crystal form. J Mol Biol. 2004;343:1409–1438. doi: 10.1016/j.jmb.2004.08.090. [DOI] [PubMed] [Google Scholar]
  • 9.Okada T, Fujiyoshi Y, Silow M, Navarro J, Landau EM, Shichida Y. Functional role of internal water molecules in rhodopsin revealed by X-ray crystallography. Proc Natl Acad Sci USA. 2002;99:5982–5987. doi: 10.1073/pnas.082666399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.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. doi: 10.1016/j.jmb.2004.07.044. [DOI] [PubMed] [Google Scholar]
  • 11.Wess J. G-protein-coupled receptors: molecular mechanisms involved in receptor activation and selectivity of G-protein recognition. FASEB J. 1997;11:346–354. [PubMed] [Google Scholar]
  • 12.Iiri T, Farfel Z, Bourne HR. G-protein diseases furnish a model for the turn-on switch. Nature. 1998;394:35–38. doi: 10.1038/27831. [DOI] [PubMed] [Google Scholar]
  • 13.Menon ST, Han M, Sakmar TP. Rhodopsin: structural basis of molecular physiology. Physiol Rev. 2001;81:1659–1688. doi: 10.1152/physrev.2001.81.4.1659. [DOI] [PubMed] [Google Scholar]
  • 14.Lewis JW, Kliger DS. Photointermediates of visual pigments. J Bioenerg Biomembr. 1992;24:201–210. doi: 10.1007/BF00762678. [DOI] [PubMed] [Google Scholar]
  • 15.Schertler GF. Structure of rhodopsin and the metarhodopsin I photointermediate. Curr Opin Struct Biol. 2005;15:408–415. doi: 10.1016/j.sbi.2005.07.010. [DOI] [PubMed] [Google Scholar]
  • 16.Bramblett RD, Panu AM, Ballesteros JA, Reggio PH. Construction of a 3D model of the cannabinoid CB1 receptor: determination of helix ends and helix orientation. Life Sci. 1995;56:1971–1982. doi: 10.1016/0024-3205(95)00178-9. [DOI] [PubMed] [Google Scholar]
  • 17.Ballesteros JA, Weinstein H. Analysis and refinement of criteria for predicting the structure and relative orientations of transmembranal helical domains. Biophys J. 1992;62:107–109. doi: 10.1016/S0006-3495(92)81794-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.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. doi: 10.1146/annurev.biophys.29.1.291. [DOI] [PubMed] [Google Scholar]
  • 19.Sali A, Blundell TL. Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol. 1993;234:779–815. doi: 10.1006/jmbi.1993.1626. [DOI] [PubMed] [Google Scholar]
  • 20.Fiser A, Do RK, Sali A. Modeling of loops in protein structures. Protein Sci. 2000;9:1753–1773. doi: 10.1110/ps.9.9.1753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Ballesteros JA, Shi L, Javitch JA. Structural mimicry in G protein-coupled receptors: implications of the high-resolution structure of rhodopsin for structure-function analysis of rhodopsin-like receptors. Mol Pharmacol. 2001;60:1–19. [PubMed] [Google Scholar]
  • 22.Zhang R, Hurst DP, Barnett-Norris J, Reggio PH, Song ZH. Cysteine 2.59(89) in the second transmembrane domain of human CB2 receptor is accessible within the ligand binding crevice: evidence for possible CB2 deviation from a rhodopsin template. Mol Pharmacol. 2005;68:69–83. doi: 10.1124/mol.104.007823. [DOI] [PubMed] [Google Scholar]
  • 23.Ballesteros JA, Deupi X, Olivella M, Haaksma EE, Pardo L. Serine and threonine residues bend alpha-helices in the chi(1)=g(-) conformation. Biophys J. 2000;79:2754–2760. doi: 10.1016/S0006-3495(00)76514-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Guarnieri F, Weinstein H. Conformational memories and the exploration of biologically relevant peptide conformations: an illustration for the gonadotropin-releasing hormone. J Am Chem Soc. 1996;118:5580–5589. doi: 10.1021/ja952745o. [DOI] [Google Scholar]
  • 25.Shi L, Liapakis G, Xu R, Guarnieri F, Ballesteros JA, Javitch JA. Beta 2 adrenergic receptor activation. Modulation of the proline kink in transmembrane 6 by a rotamer toggle switch. J Biol Chem. 2002;277:40989–40996. doi: 10.1074/jbc.M206801200. [DOI] [PubMed] [Google Scholar]
  • 26.Barnett-Norris J, Hurst DP, Buehner K, Ballesteros JA, Guarnieri F, Reggio PH. Agonist alkyl tail interaction with cannabinoid CB1 receptor V6.43/I6.46 groove induces a Helix 6 active conformation. Int J Quantum Chem. 2002;88:76–86. doi: 10.1002/qua.10093. [DOI] [Google Scholar]
  • 27.Eisenberg D, Weiss RM, Terwilliger TC. The hydrophobic moment detects periodicity in protein hydrophobicity. Proc Natl Acad Sci USA. 1984;81:140–144. doi: 10.1073/pnas.81.1.140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Komiya H, Yeates TO, Rees DC, Allen JP, Feher G. Structure of the reaction center from Rhodobacter sphaeroides R-26 and 2.4.1: symmetry relations and sequence comparisons between different species. Proc Natl Acad Sci USA. 1988;85:9012–9016. doi: 10.1073/pnas.85.23.9012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Donnelly D, Johnson MS, Blundell TL, Saunders J. An analysis of the periodicity of conserved residues in sequence alignments of G-protein coupled receptors: implications for the three-dimensional structure. FEBS Lett. 1989;251:109–116. doi: 10.1016/0014-5793(89)81438-3. [DOI] [PubMed] [Google Scholar]
  • 30.Donnelly D, Overington JP, Ruffle SV, Nugent JH, Blundell TL. Modeling alpha-helical transmembrane domains: the calculation and use of substitution tables for lipid-facing residues. Protein Sci. 1993;2:55–70. doi: 10.1002/pro.5560020106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Baldwin J. The probable arrangement of the helices in G protein-coupled receptors. EMBO J. 1993;12:1693–1703. doi: 10.1002/j.1460-2075.1993.tb05814.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Schertler GF, Villa C, Henderson R. Projection structure of rhodopsin. Nature. 1993;362:770–772. doi: 10.1038/362770a0. [DOI] [PubMed] [Google Scholar]
  • 33.Trabanino RJ, Hall SE, Vaidehi N, Floriano WB, Kam VW, Goddard WA. First principles predictions of the structure and function of g-protein-coupled receptors: validation for bovine rhodopsin. Biophys J. 2004;86:1904–1921. doi: 10.1016/S0006-3495(04)74256-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Kalani MY, Vaidehi N, Hall SE, et al. The predicted 3D structure of the human D2 dopamine receptor and the binding site and binding affinities for agonists and antagonists. Proc Natl Acad Sci USA. 2004;101:3815–3820. doi: 10.1073/pnas.0400100101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Freddolino PL, Kalani MY, Vaidehi N, et al. Predicted 3D structure for the human beta 2 adrenergic receptor and its binding site for agonists and antagonists. Proc Natl Acad Sci USA. 2004;101:2736–2741. doi: 10.1073/pnas.0308751101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Ruprecht JJ, Mielke T, Vogel R, Villa C, Schertler GF. Electron crystallography reveals the structure of metarhodopsin I. EMBO J. 2004;23:3609–3620. doi: 10.1038/sj.emboj.7600374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Gether U, Kobilka BK. G protein-coupled receptors, II: mechanism of agonist activation. J Biol Chem. 1998;273:17979–17982. doi: 10.1074/jbc.273.29.17979. [DOI] [PubMed] [Google Scholar]
  • 38.Arnis S, Fahmy K, Hofmann KP, Sakmar TP. A conserved carboxylic acid group mediates light-dependent proton uptake and signaling by rhodopsin. J Biol Chem. 1994;269:23879–23881. [PubMed] [Google Scholar]
  • 39.Ghanouni P, Steenhuis JJ, Farrens DL, Kobilka BK. Agonist-induced conformational changes in the G-protein-coupling domain of the beta 2 adrenergic receptor. Proc Natl Acad Sci USA. 2001;98:5997–6002. doi: 10.1073/pnas.101126198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Farrens D, Altenbach C, Ynag K, Hubbell W, Khorana H. Requirement of rigid-body motion of transmembrane helices for light activation of rhodopsin. Science. 1996;274:768–770. doi: 10.1126/science.274.5288.768. [DOI] [PubMed] [Google Scholar]
  • 41.Gether U, Lin S, Ghanouni P, Ballesteros J, Weinstein H, Kobilka B. Agonists induce conformational changes in transmembrane domains III and VI of the beta2 adrenoceptor. EMBO J. 1997;16:6737–6747. doi: 10.1093/emboj/16.22.6737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Ballesteros J, Jensen A, Liapakis G, et al. Activation of theb2 adrenergic receptor involves disruption of an ionic link between the cytoplasmic ends of transmembrane segments 3 and 6. J Biol Chem. 2001;276:29171–29177. doi: 10.1074/jbc.M103747200. [DOI] [PubMed] [Google Scholar]
  • 43.Visiers I, Ebersole BJ, Dracheva S, Ballesteros J, Sealfon SC, Weinstein H. Structural motifs as functional microdomains in G-protein-coupled receptors: energetic considerations in the mechanism of activation of the serotonin 5-HT2a receptor by disruption of the ionic lock of the arginine cage. Int J Quantum Chem. 2002;88:65–75. doi: 10.1002/qua.10078. [DOI] [Google Scholar]
  • 44.Jensen AD, Guarnieri F, Rasmussen SG, Asmar F, Ballesteros JA, Gether U. Agonist-induced conformational changes at the cytoplasmic side of transmembrane segment 6 in the beta 2 adrenergic receptor mapped by site-selective fluorescent labeling. J Biol Chem. 2001;276:9279–9290. doi: 10.1074/jbc.M004871200. [DOI] [PubMed] [Google Scholar]
  • 45.McAllister SD, Hurst DP, Barnett-Norris J, Lynch D, Reggio PH, Abood ME. Structural mimicry in class A G protein-coupled receptor rotamer toggle switches: the importance of the F3.36(201)/W6.48(357) interaction in cannabinoid CB1 receptor activation. J Biol Chem. 2004;279:48024–48037. doi: 10.1074/jbc.M406648200. [DOI] [PubMed] [Google Scholar]
  • 46.Gouldson PR, Kidley NJ, Bywater RP, et al. Toward the active conformations of rhodopsin and the beta2-adrenergic receptor. Proteins. 2004;56:67–84. doi: 10.1002/prot.20108. [DOI] [PubMed] [Google Scholar]
  • 47.Klein-Seetharaman J, Yanamala NV, Javeed F, et al. Differential dynamics in the G protein-coupled receptor rhodopsin revealed by solution NMR. Proc Natl Acad Sci USA. 2004;101:3409–3413. doi: 10.1073/pnas.0308713101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Borhan B, Souto ML, Imai H, Shichida Y, Nakanishi K. Movement of retinal along the visual transduction path. Science. 2000;288:2209–2212. doi: 10.1126/science.288.5474.2209. [DOI] [PubMed] [Google Scholar]
  • 49.Lin S, Sakmar T. Specific tryptophan UV-absorbance changes are probes of the transition of rhodopsin to its active state. Biochemistry. 1996;35:11149–11159. doi: 10.1021/bi960858u. [DOI] [PubMed] [Google Scholar]
  • 50.Singh R, Hurst DP, Barnett-Norris J, Lynch DL, Reggio PH, Guarnieri F. Activation of the cannabinoid CB1 receptor may involve a W6.48/F3.36 rotamer toggle switch. J Pept Res. 2002;60:357–370. doi: 10.1034/j.1399-3011.2002.21065.x. [DOI] [PubMed] [Google Scholar]
  • 51.Ghanouni P, Gryczynski Z, Steenhuis JJ, et al. Functionally different agonists induce distinct conformations in the G protein coupling domain of the beta 2 adrenergic receptor. J Biol Chem. 2001;276:24433–24436. doi: 10.1074/jbc.C100162200. [DOI] [PubMed] [Google Scholar]
  • 52.Mukhopadhyay S, Howlett AC. Chemically distinct ligands promote differential CB1 cannabinoid receptor-Gi protein interactions. Mol Pharmacol. 2005;67:2016–2024. doi: 10.1124/mol.104.003558. [DOI] [PubMed] [Google Scholar]
  • 53.Paterlini MG. The function of the extracellular regions in opioid receptor binding: insights from computational biology. Curr Top Med Chem. 2005;5:357–367. doi: 10.2174/1568026053544579. [DOI] [PubMed] [Google Scholar]
  • 54.Tosatto SC, Bindewald E, Hesser J, Manner R. A divide and conquer approach to fast loop modeling. Protein Eng. 2002;15:279–286. doi: 10.1093/protein/15.4.279. [DOI] [PubMed] [Google Scholar]
  • 55.Xiang Z, Soto CS, Honig B. Evaluating conformational free energies: the colony energy and its application to the problem of loop prediction. Proc Natl Acad Sci USA. 2002;99:7432–7437. doi: 10.1073/pnas.102179699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Mehler EL, Periole X, Hassan SA, Weinstein H. Key issues in the computational simulation of GPCR function: representation of loop domains. J Comput Aided Mol Des. 2002;16:841–853. doi: 10.1023/A:1023845015343. [DOI] [PubMed] [Google Scholar]
  • 57.Hassan SA, Mehler EL, Weinstein H. Structure calculation of protein segments connecting domains with defined secondary structure: a simulated annealing Monte Carlo combined with biased scaled collective variables technique. In: Schlick T, Gan HH, editors. Computational Methods for Macromolecules: Challenges and Applications, Vol 24. New York, NY: Springer Verlag; 2002. pp. 197–231. [Google Scholar]
  • 58.Hassan SA, Guarnieri F, Mehler EL. A general treatment of solvent effects based on screened coulomb potentials. J Phys Chem B. 2000;104:6478–6489. doi: 10.1021/jp993895e. [DOI] [Google Scholar]
  • 59.Chabre M, le Maire M. Monomeric G-protein-coupled receptor as a functional unit. Biochemistry. 2005;44:9395–9403. doi: 10.1021/bi050720o. [DOI] [PubMed] [Google Scholar]
  • 60.Terrillon S, Bouvier M. Roles of G-protein-coupled receptor dimerization. EMBO Rep. 2004;5:30–34. doi: 10.1038/sj.embor.7400052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Bulenger S, Marullo S, Bouvier M. Emerging role of homo- and heterodimerization in G-protein-coupled receptor biosynthesis and maturation. Trends Pharmacol Sci. 2005;26:131–137. doi: 10.1016/j.tips.2005.01.004. [DOI] [PubMed] [Google Scholar]
  • 62.Reddy PS, Corley RB. Assembly, sorting, and exit of oligomeric proteins from the endoplasmic reticulum. Bioessays. 1998;20:546–554. doi: 10.1002/(SICI)1521-1878(199807)20:7<546::AID-BIES5>3.0.CO;2-I. [DOI] [PubMed] [Google Scholar]
  • 63.Marshall FH, Jones KA, Kaupmann K, Bettler B. GABAB receptors—the first 7TM heterodimers. Trends Pharmacol Sci. 1999;20:396–399. doi: 10.1016/S0165-6147(99)01383-8. [DOI] [PubMed] [Google Scholar]
  • 64.Margeta-Mitrovic M, Jan YN, Jan LY. A trafficking checkpoint controls GABA(B) receptor heterodimerization. Neuron. 2000;27:97–106. doi: 10.1016/S0896-6273(00)00012-X. [DOI] [PubMed] [Google Scholar]
  • 65.Milligan G. Oligomerisation of G-protein-coupled receptors. J Cell Sci. 2001;114:1265–1271. doi: 10.1242/jcs.114.7.1265. [DOI] [PubMed] [Google Scholar]
  • 66.Roess DA, Smith SM. Self-association and raft localization of functional luteinizing hormone receptors. Biol Reprod. 2003;69:1765–1770. doi: 10.1095/biolreprod.103.018846. [DOI] [PubMed] [Google Scholar]
  • 67.Latif R, Graves P, Davies TF. Ligand-dependent inhibition of oligomerization at the human thyrotropin receptor. J Biol Chem. 2002;277:45059–45067. doi: 10.1074/jbc.M206693200. [DOI] [PubMed] [Google Scholar]
  • 68.Terrillon S, Durroux T, Mouillac B, et al. Oxytocin and vasopressin VIa and V2 receptors form constitutive homo- and heterodimers during biosynthesis. Mol Endocrinol. 2003;17:677–691. doi: 10.1210/me.2002-0222. [DOI] [PubMed] [Google Scholar]
  • 69.Fotiadis D, Liang Y, Filipek S, Saperstein DA, Engel A, Palczewski K. Atomic-force microscopy: rhodopsin dimers in native disc membranes. Nature. 2003;421:127–128. doi: 10.1038/421127a. [DOI] [PubMed] [Google Scholar]
  • 70.Liang Y, Fotiadis D, Filipek S, Saperstein DA, Palczewski K, Engel A. Organization of the G protein-coupled receptors rhodopsin and opsin in native membranes. J Biol Chem. 2003;278:21655–21662. doi: 10.1074/jbc.M302536200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Jordan BA, Devi LA. G-protein-coupled receptor heterodimerization modulates receptor function. Nature. 1999;399:697–700. doi: 10.1038/21441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Galvez T, Duthey B, Kniazeff J, et al. Allosteric interactions between GB1 and GB2 subunits are required for optimal GABA(B) receptor function. EMBO J. 2001;20:2152–2159. doi: 10.1093/emboj/20.9.2152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Gomes I, Jordan BA, Gupta A, Trapaidze N, Nagy V, Devi LA. Heterodimerization of mu and delta opioid receptors: a role in opiate synergy. J Neurosci. 2000;20:RC110–RC110. doi: 10.1523/JNEUROSCI.20-22-j0007.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Maggio R, Barbier P, Colelli A, Salvadori F, Demontis G, Corsini GU. G protein-linked receptors: pharmacological evidence for the formation of heterodimers. J Pharmacol Exp Ther. 1999;291:251–257. [PubMed] [Google Scholar]
  • 75.Rocheville M, Lange DC, Kumar U, Patel SC, Patel RC, Patel YC. Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science. 2000;288:154–157. doi: 10.1126/science.288.5463.154. [DOI] [PubMed] [Google Scholar]
  • 76.Franco R, Ferre S, Agnati L, et al. Evidence for adenosine/dopamine receptor interactions: indications for heteromerization. Neuropsychopharmacology. 2000;23:S50–S59. doi: 10.1016/S0893-133X(00)00144-5. [DOI] [PubMed] [Google Scholar]
  • 77.Nelson G, Chandrashekar J, Hoon MA, et al. An amino-acid taste receptor. Nature. 2002;416:199–202. doi: 10.1038/nature726. [DOI] [PubMed] [Google Scholar]
  • 78.Nelson G, Hoon MA, Chandrashekar J, Zhang Y, Ryba NJ, Zuker CS. Mammalian sweet taste receptors. Cell. 2001;106:381–390. doi: 10.1016/S0092-8674(01)00451-2. [DOI] [PubMed] [Google Scholar]
  • 79.Mellado M, Rodriguez-Frade JM, Vila-Coro AJ, et al. Chemokine receptor homo- or heterodimerization activates distinct signaling pathways. EMBO J. 2001;20:2497–2507. doi: 10.1093/emboj/20.10.2497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.AbdAlla S, Lother H, Quitterer U. AT1-receptor heterodimers show enhanced G-protein activation and altered receptor sequestration. Nature. 2000;407:94–98. doi: 10.1038/35024095. [DOI] [PubMed] [Google Scholar]
  • 81.Gines S, Hillion J, Torvinen M, et al. Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes. Proc Natl Acad Sci USA. 2000;97:8606–8611. doi: 10.1073/pnas.150241097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Pfeiffer M, Koch T, Schroder H, et al. Homo- and heterodimerization of somatostatin receptor subtypes. Inactivation of sst(3) receptor function by heterodimerization with sst(2A) J Biol Chem. 2001;276:14027–14036. doi: 10.1074/jbc.M006084200. [DOI] [PubMed] [Google Scholar]
  • 83.Kearn CS, Blake-Palmer K, Daniel E, Mackie K, Glass M. Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors enhances heterodimer formation: a mechanism for receptor cross-talk? Mol Pharmacol. 2005;67:1697–1704. doi: 10.1124/mol.104.006882. [DOI] [PubMed] [Google Scholar]
  • 84.Hamm HE. How activated receptors couple to G proteins. Proc Natl Acad Sci USA. 2001;98:4819–4821. doi: 10.1073/pnas.011099798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Baneres JL, Parello J. Structure-based analysis of GPCR function: evidence for a novel pentameric assembly between the dimeric leukotriene B4 receptor BLT1 and the G-protein. J Mol Biol. 2003;329:815–829. doi: 10.1016/S0022-2836(03)00439-X. [DOI] [PubMed] [Google Scholar]
  • 86.Rocheville M, Lange DC, Kumar U, Sasi R, Patel RC, Patel YC. Subtypes of the somatostatin receptor assemble as functional homo- and heterodimers. J Biol Chem. 2000;275:7862–7869. doi: 10.1074/jbc.275.11.7862. [DOI] [PubMed] [Google Scholar]
  • 87.Xu J, He J, Castleberry AM, Balasubramanian S, Lau AG, Hall RA. Heterodimerization of alpha 2A- and beta 1-adrenergic receptors. J Biol Chem. 2003;278:10770–10777. doi: 10.1074/jbc.M207968200. [DOI] [PubMed] [Google Scholar]
  • 88.Stanasila L, Perez JB, Vogel H, Cotecchia S. Oligomerization of the alpha 1a- and alpha 1b-adrenergic receptor subtypes. Potential implications in receptor internalization. J Biol Chem. 2003;278:40239–40251. doi: 10.1074/jbc.M306085200. [DOI] [PubMed] [Google Scholar]
  • 89.Barki-Harrington L, Luttrell LM, Rockman HA. Dual inhibition of beta-adrenergic and angiotensin II receptors by a single antagonist: a functional role for receptor-receptor interaction in vivo. Circulation. 2003;108:1611–1618. doi: 10.1161/01.CIR.0000092166.30360.78. [DOI] [PubMed] [Google Scholar]
  • 90.Schulz A, Grosse R, Schultz G, Gudermann T, Schoneberg T. Structural implication for receptor oligomerization from functional reconstitution studies of mutant V2 vasopressin receptors. J Biol Chem. 2000;275:2381–2389. doi: 10.1074/jbc.275.4.2381. [DOI] [PubMed] [Google Scholar]
  • 91.Lee SP, O'Dowd BF, Ng GY, et al. Inhibition of cell surface expression by mutant receptors demonstrates that D2 dopamine receptors exist as oligomers in the cell. Mol Pharmacol. 2000;58:120–128. doi: 10.1124/mol.58.1.120. [DOI] [PubMed] [Google Scholar]
  • 92.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. doi: 10.1021/bi016029c. [DOI] [PubMed] [Google Scholar]
  • 93.Hadac EM, Ji Z, Pinon DI, Henne RM, Lybrand TP, Miller LJ. A peptide agonist acts by occupation of a monomeric G protein-coupled receptor: dual sites of covalent attachment to domains near TM1 and TM7 of the same molecule make biologically significant domain-swapped dimerization unlikely. J Med Chem. 1999;42:2105–2111. doi: 10.1021/jm980732q. [DOI] [PubMed] [Google Scholar]
  • 94.Overton MC, Blumer KJ. The extracellular N-terminal domain and transmembrane domains 1 and 2 mediate oligomerization of a yeast G protein-coupled receptor. J Biol Chem. 2002;277:41463–41472. doi: 10.1074/jbc.M205368200. [DOI] [PubMed] [Google Scholar]
  • 95.Guo W, Shi L, Javitch JA. The fourth transmembrane segment forms the interface of the dopamine D2 receptor homodimer. J Biol Chem. 2003;278:4385–4388. doi: 10.1074/jbc.C200679200. [DOI] [PubMed] [Google Scholar]
  • 96.Guo W, Shi L, Filizola M, Weinstein H, Javitch JA. Crosstalk in G protein-coupled receptors: changes at the transmembrane homodimer interface determine activation. Proc Natl Acad Sci USA. 2005;102:17495–17500. doi: 10.1073/pnas.0508950102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.Gouldson PR, Higgs C, Smith RE, Dean MK, Gkoutos GV, Reynolds CA. Dimerization and domain swapping in G-protein-coupled receptors: a computational study. Neuropsychopharmacology. 2000;23:S60–S77. doi: 10.1016/S0893-133X(00)00153-6. [DOI] [PubMed] [Google Scholar]
  • 98.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 USA. 1993;90:3103–3107. doi: 10.1073/pnas.90.7.3103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99.Ridge KD, Lee SS, Abdulaev NG. Examining rhodopsin folding and assembly through expression of polypeptide fragments. J Biol Chem. 1996;271:7860–7867. doi: 10.1074/jbc.271.13.7860. [DOI] [PubMed] [Google Scholar]
  • 100.Kobilka BK, Kobilka TS, Daniel K, Regan JW, Caron MG, Lefkowitz RJ. Chimeric alpha 2-,beta 2-adrenergic receptors: delineation of domains involved in effector coupling and ligand binding specificity. Science. 1998;240:1310–1316. doi: 10.1126/science.2836950. [DOI] [PubMed] [Google Scholar]
  • 101.Schoneberg T, Liu J, Wess J. Plasma membrane localization and functional rescue of truncated forms of a G protein-coupled receptor. J Biol Chem. 1995;270:18000–18006. doi: 10.1074/jbc.270.30.18000. [DOI] [PubMed] [Google Scholar]
  • 102.Schoneberg T, Yun J, Wenkert D, Wess J. Functional rescue of mutant V2 vasopressin receptors causing nephrogenic diabetes insipidus by a co-expressed receptor polypeptide. EMBO J. 1996;15:1283–1291. [PMC free article] [PubMed] [Google Scholar]
  • 103.Gudermann T, Schoneberg T, Schultz G. Functional and structural complexity of signal transduction via G-protein-coupled receptors. Annu Rev Neurosci. 1997;20:399–427. doi: 10.1146/annurev.neuro.20.1.399. [DOI] [PubMed] [Google Scholar]
  • 104.Nielsen SM, Elling CE, Schwartz TW. Split-receptors in the tachykinin neurokinin-1 system-mutational analysis of intracellular loop 3. Eur J Biochem. 1998;251:217–226. doi: 10.1046/j.1432-1327.1998.2510217.x. [DOI] [PubMed] [Google Scholar]
  • 105.Bakker RA, Dees G, Carrillo JJ, et al. Domain swapping in the human histamine H1 receptor. J Pharmacol Exp Ther. 2004;311:131–138. doi: 10.1124/jpet.104.067041. [DOI] [PubMed] [Google Scholar]
  • 106.Maggio R, Barbier P, Fornai F, Corsini GU. Functional role of the third cytoplasmic loop in muscarinic receptor dimerization. J Biol Chem. 1996;271:31055–31060. doi: 10.1074/jbc.271.49.31055. [DOI] [PubMed] [Google Scholar]
  • 107.Filizola M, Weinstein H. The study of G-protein coupled receptor oligomerization with computational modeling and bioinformatics. FEBS J. 2005;272:2926–2938. doi: 10.1111/j.1742-4658.2005.04730.x. [DOI] [PubMed] [Google Scholar]
  • 108.Pazos F, Helmer-Citterich M, Ausiello G, Valencia A. Correlated mutations contain information about protein-protein interaction. J Mol Biol. 1997;271:511–523. doi: 10.1006/jmbi.1997.1198. [DOI] [PubMed] [Google Scholar]
  • 109.Gouldson PR, Dean MK, Snell CR, Bywater RP, Gkoutos G, Reynolds CA. Lipid-facing correlated mutations and dimerization in G-protein coupled receptors. Protein Eng. 2001;14:759–767. doi: 10.1093/protein/14.10.759. [DOI] [PubMed] [Google Scholar]
  • 110.Filizola M, Olmea O, Weinstein H. Prediction of heterodimerization interfaces of G-protein coupled receptors with a new subtractive correlated mutation method. Protein Eng. 2002;15:881–885. doi: 10.1093/protein/15.11.881. [DOI] [PubMed] [Google Scholar]
  • 111.Filizola M, Weinstein H. Structural models for dimerization of G-protein coupled receptors: the opioid receptor homodimers. Biopolymers. 2002;66:317–325. doi: 10.1002/bip.10311. [DOI] [PubMed] [Google Scholar]
  • 112.Olmea O, Valencia A. Improving contact predictions by the combination of correlated mutations and other sources of sequence information. Fold Des. 1997;2:S25–S32. doi: 10.1016/S1359-0278(97)00060-6. [DOI] [PubMed] [Google Scholar]
  • 113.Barnett-Norris J, Reggio PH. Identification of possible CB1/dopamine D2 heterodimer interfaces using correlated mutation analysis; FL. Burlington, VT: International Cannabinoid Research Society; 2005. pp. 101–101. [Google Scholar]
  • 114.Lichtarge O, Bourne HR, Cohen FE. Evolutionarily conserved Galphabetagamma binding surfaces support a model of the G proteinreceptor complex. Proc Natl Acad Sci USA. 1996;93:7507–7511. doi: 10.1073/pnas.93.15.7507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 115.Lichtarge O, Bourne HR, Cohen FE. An evolutionary trace method defines binding surfaces common to protein families. J Mol Biol. 1996;257:342–358. doi: 10.1006/jmbi.1996.0167. [DOI] [PubMed] [Google Scholar]
  • 116.Lichtarge O, Yamamoto KR, Cohen FE. Identification of functional surfaces of the zinc binding domains of intracellular receptors. J Mol Biol. 1997;274:325–337. doi: 10.1006/jmbi.1997.1395. [DOI] [PubMed] [Google Scholar]
  • 117.Livingstone CD, Barton GJ. Protein sequence alignments: a strategy for the hierarchical analysis of residue conservation. Comput Appl Biosci. 1993;9:745–756. doi: 10.1093/bioinformatics/9.6.745. [DOI] [PubMed] [Google Scholar]
  • 118.Madabushi S, Gross AK, Philippi A, Meng EC, Wensel TG, Lichtarge O. Evolutionary trace of G protein-coupled receptors reveals clusters of residues that determine global and class-specific functions. J Biol Chem. 2004;279:8126–8132. doi: 10.1074/jbc.M312671200. [DOI] [PubMed] [Google Scholar]
  • 119.Chothia C, Lesk AM. The relation between the divergence of sequence and structure in proteins. EMBO J. 1986;5:823–826. doi: 10.1002/j.1460-2075.1986.tb04288.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 120.Koshi JM, Mindell DP, Goldstein RA. Using physical-chemistry-based substitution models in phylogenetic analyses of HIV-1 subtypes. Mol Biol Evol. 1999;16:173–179. doi: 10.1093/oxfordjournals.molbev.a026100. [DOI] [PubMed] [Google Scholar]
  • 121.Koshi JM, Goldstein RA. Models of natural mutations including site heterogeneity. Proteins. 1998;32:289–295. doi: 10.1002/(SICI)1097-0134(19980815)32:3<289::AID-PROT4>3.0.CO;2-D. [DOI] [PubMed] [Google Scholar]
  • 122.Koshi JM, Goldstein RA. Context-dependent optimal substitution matrices. Protein Eng. 1995;8:641–645. doi: 10.1093/peds/8.7.641. [DOI] [PubMed] [Google Scholar]
  • 123.Soyer OS, Dimmic MW, Neubig RR, Goldstein RA. Dimerization in aminergic G-protein-coupled receptors: application of a hidden-site class model of evolution. Biochemistry. 2003;42:14522–14531. doi: 10.1021/bi035097r. [DOI] [PubMed] [Google Scholar]

Articles from The AAPS Journal are provided here courtesy of American Association of Pharmaceutical Scientists

RESOURCES