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Journal of Computer-Aided Molecular Design

, Volume 30, Issue 6, pp 489–512 | Cite as

Molecular dynamics simulations and structure-based network analysis reveal structural and functional aspects of G-protein coupled receptor dimer interactions

  • Fotis A. Baltoumas
  • Margarita C. Theodoropoulou
  • Stavros J. HamodrakasEmail author
Article

Abstract

A significant amount of experimental evidence suggests that G-protein coupled receptors (GPCRs) do not act exclusively as monomers but also form biologically relevant dimers and oligomers. However, the structural determinants, stoichiometry and functional importance of GPCR oligomerization remain topics of intense speculation. In this study we attempted to evaluate the nature and dynamics of GPCR oligomeric interactions. A representative set of GPCR homodimers were studied through Coarse-Grained Molecular Dynamics simulations, combined with interface analysis and concepts from network theory for the construction and analysis of dynamic structural networks. Our results highlight important structural determinants that seem to govern receptor dimer interactions. A conserved dynamic behavior was observed among different GPCRs, including receptors belonging in different GPCR classes. Specific GPCR regions were highlighted as the core of the interfaces. Finally, correlations of motion were observed between parts of the dimer interface and GPCR segments participating in ligand binding and receptor activation, suggesting the existence of mechanisms through which dimer formation may affect GPCR function. The results of this study can be used to drive experiments aimed at exploring GPCR oligomerization, as well as in the study of transmembrane protein–protein interactions in general.

Keywords

G-protein coupled receptors Oligomerization Molecular dynamics Network analysis 

Notes

Acknowledgments

We would like to thank the scientific and administrative staff of the “Bioinformatics” Master’s Program at the Faculty of Biology of the University of Athens, for its generous support. M.C.T. was financially supported as a postdoctoral fellow by Greek State Scholarships Foundation, through the Siemens Program: “IKY Fellowships of Excellence for Postgraduate Studies in Greece – Siemens Program (2014–2015)”. This work was supported by computational time granted from the Greek Research & Technology Network (GRNET) in the National HPC facility—ARIS under project ID “PR001025-M.D.S.B.M.S.”. Finally, we would like to sincerely thank the anonymous reviewers for their very valuable and constructive criticism, which helped us to considerably improve the manuscript, as well as the Editor-in-Chief for properly handling it. The authors declare no conflicts of interest.

Supplementary material

10822_2016_9919_MOESM1_ESM.pdf (5.2 mb)
Supplementary material 1 (PDF 5345 kb)

References

  1. 1.
    Rosenbaum DM, Rasmussen SG, Kobilka BK (2009) The structure and function of G-protein-coupled receptors. Nature 459(7245):356–363. doi: 10.1038/nature08144 CrossRefGoogle Scholar
  2. 2.
    Cherezov V, Abola E, Stevens RC (2010) Recent progress in the structure determination of GPCRs, a membrane protein family with high potential as pharmaceutical targets. Methods Mol Biol 654:141–168. doi: 10.1007/978-1-60761-762-4_8 CrossRefGoogle Scholar
  3. 3.
    Oldham WM, Hamm HE (2008) Heterotrimeric G protein activation by G-protein-coupled receptors. Nat Rev Mol Cell Biol 9(1):60–71. doi: 10.1038/nrm2299 CrossRefGoogle Scholar
  4. 4.
    Kolakowski LF Jr (1994) GCRDb: a G-protein-coupled receptor database. Recept Channels 2(1):1–7Google Scholar
  5. 5.
    Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M (2000) Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289(5480):739–745CrossRefGoogle Scholar
  6. 6.
    Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC (2007) High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 318(5854):1258–1265. doi: 10.1126/science.1150577 CrossRefGoogle Scholar
  7. 7.
    Warne T, Serrano-Vega MJ, Baker JG, Moukhametzianov R, Edwards PC, Henderson R, Leslie AG, Tate CG, Schertler GF (2008) Structure of a beta1-adrenergic G-protein-coupled receptor. Nature 454(7203):486–491. doi: 10.1038/nature07101 CrossRefGoogle Scholar
  8. 8.
    Xu F, Wu H, Katritch V, Han GW, Jacobson KA, Gao ZG, Cherezov V, Stevens RC (2011) Structure of an agonist-bound human A2A adenosine receptor. Science 332(6027):322–327. doi: 10.1126/science.1202793 CrossRefGoogle Scholar
  9. 9.
    Granier S, Manglik A, Kruse AC, Kobilka TS, Thian FS, Weis WI, Kobilka BK (2012) Structure of the delta-opioid receptor bound to naltrindole. Nature 485(7398):400–404. doi: 10.1038/nature11111 CrossRefGoogle Scholar
  10. 10.
    Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S (2012) Crystal structure of the mu-opioid receptor bound to a morphinan antagonist. Nature 485(7398):321–326. doi: 10.1038/nature10954 CrossRefGoogle Scholar
  11. 11.
    Wu H, Wacker D, Mileni M, Katritch V, Han GW, Vardy E, Liu W, Thompson AA, Huang XP, Carroll FI, Mascarella SW, Westkaemper RB, Mosier PD, Roth BL, Cherezov V, Stevens RC (2012) Structure of the human kappa-opioid receptor in complex with JDTic. Nature 485(7398):327–332. doi: 10.1038/nature10939 CrossRefGoogle Scholar
  12. 12.
    Wang C, Wu H, Katritch V, Han GW, Huang XP, Liu W, Siu FY, Roth BL, Cherezov V, Stevens RC (2013) Structure of the human smoothened receptor bound to an antitumour agent. Nature 497(7449):338–343. doi: 10.1038/nature12167 CrossRefGoogle Scholar
  13. 13.
    Hollenstein K, Kean J, Bortolato A, Cheng RK, Dore AS, Jazayeri A, Cooke RM, Weir M, Marshall FH (2013) Structure of class B GPCR corticotropin-releasing factor receptor 1. Nature 499(7459):438–443. doi: 10.1038/nature12357 CrossRefGoogle Scholar
  14. 14.
    Siu FY, He M, de Graaf C, Han GW, Yang D, Zhang Z, Zhou C, Xu Q, Wacker D, Joseph JS, Liu W, Lau J, Cherezov V, Katritch V, Wang MW, Stevens RC (2013) Structure of the human glucagon class B G-protein-coupled receptor. Nature 499(7459):444–449. doi: 10.1038/nature12393 CrossRefGoogle Scholar
  15. 15.
    Dore AS, Okrasa K, Patel JC, Serrano-Vega M, Bennett K, Cooke RM, Errey JC, Jazayeri A, Khan S, Tehan B, Weir M, Wiggin GR, Marshall FH (2014) Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. Nature 511(7511):557–562. doi: 10.1038/nature13396 CrossRefGoogle Scholar
  16. 16.
    Wu H, Wang C, Gregory KJ, Han GW, Cho HP, Xia Y, Niswender CM, Katritch V, Meiler J, Cherezov V, Conn PJ, Stevens RC (2014) Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science 344(6179):58–64. doi: 10.1126/science.1249489 CrossRefGoogle Scholar
  17. 17.
    Ferre S, Casado V, Devi LA, Filizola M, Jockers R, Lohse MJ, Milligan G, Pin JP, Guitart X (2014) G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives. Pharmacol Rev 66(2):413–434. doi: 10.1124/pr.113.008052 CrossRefGoogle Scholar
  18. 18.
    Franco R, Casado V, Cortes A, Ferrada C, Mallol J, Woods A, Lluis C, Canela EI, Ferre S (2007) Basic concepts in G-protein-coupled receptor homo- and heterodimerization. Sci World J 7:48–57. doi: 10.1100/tsw.2007.197 CrossRefGoogle Scholar
  19. 19.
    Borroto-Escuela DO, Brito I, Romero-Fernandez W, Di Palma M, Oflijan J, Skieterska K, Duchou J, Van Craenenbroeck K, Suarez-Boomgaard D, Rivera A, Guidolin D, Agnati LF, Fuxe K (2014) The G protein-coupled receptor heterodimer network (GPCR-HetNet) and its hub components. Int J Mol Sci 15(5):8570–8590. doi: 10.3390/ijms15058570 CrossRefGoogle Scholar
  20. 20.
    Kniazeff J, Prezeau L, Rondard P, Pin JP, Goudet C (2011) Dimers and beyond: the functional puzzles of class C GPCRs. Pharmacol Ther 130(1):9–25. doi: 10.1016/j.pharmthera.2011.01.006 CrossRefGoogle Scholar
  21. 21.
    Dalrymple MB, Pfleger KD, Eidne KA (2008) G protein-coupled receptor dimers: functional consequences, disease states and drug targets. Pharmacol Ther 118(3):359–371. doi: 10.1016/j.pharmthera.2008.03.004 CrossRefGoogle Scholar
  22. 22.
    Niswender CM, Conn PJ (2010) Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol 50:295–322. doi: 10.1146/annurev.pharmtox.011008.145533 CrossRefGoogle Scholar
  23. 23.
    Lee CW, Ho IK (2013) Pharmacological profiles of oligomerized mu-opioid receptors. Cells 2(4):689–714. doi: 10.3390/cells2040689 CrossRefGoogle Scholar
  24. 24.
    Moreno JL, Holloway T, Gonzalez-Maeso J (2013) G protein-coupled receptor heterocomplexes in neuropsychiatric disorders. Prog Mol Biol Transl Sci 117:187–205. doi: 10.1016/B978-0-12-386931-9.00008-8 CrossRefGoogle Scholar
  25. 25.
    Wade SM, Dalman HM, Yang SZ, Neubig RR (1994) Multisite interactions of receptors and G proteins: enhanced potency of dimeric receptor peptides in modifying G protein function. Mol Pharmacol 45(6):1191–1197Google Scholar
  26. 26.
    Guo W, Shi L, Javitch JA (2003) The fourth transmembrane segment forms the interface of the dopamine D2 receptor homodimer. J Biol Chem 278(7):4385–4388. doi: 10.1074/jbc.C200679200 CrossRefGoogle Scholar
  27. 27.
    Wang HX, Konopka JB (2009) Identification of amino acids at two dimer interface regions of the alpha-factor receptor (Ste2). Biochemistry 48(30):7132–7139. doi: 10.1021/bi900424h CrossRefGoogle Scholar
  28. 28.
    Johnston JM, Aburi M, Provasi D, Bortolato A, Urizar E, Lambert NA, Javitch JA, Filizola M (2011) Making structural sense of dimerization interfaces of delta opioid receptor homodimers. Biochemistry 50(10):1682–1690. doi: 10.1021/bi101474v CrossRefGoogle Scholar
  29. 29.
    Kaczor AA, Selent J (2011) Oligomerization of G protein-coupled receptors: biochemical and biophysical methods. Curr Med Chem 18(30):4606–4634CrossRefGoogle Scholar
  30. 30.
    Hu J, Thor D, Zhou Y, Liu T, Wang Y, McMillin SM, Mistry R, Challiss RA, Costanzi S, Wess J (2012) Structural aspects of M(3) muscarinic acetylcholine receptor dimer formation and activation. FASEB J 26(2):604–616. doi: 10.1096/fj.11-191510 CrossRefGoogle Scholar
  31. 31.
    Fotiadis D, Liang Y, Filipek S, Saperstein DA, Engel A, Palczewski K (2003) Atomic-force microscopy: rhodopsin dimers in native disc membranes. Nature 421(6919):127–128. doi: 10.1038/421127a CrossRefGoogle Scholar
  32. 32.
    Liang Y, Fotiadis D, Filipek S, Saperstein DA, Palczewski K, Engel A (2003) Organization of the G protein-coupled receptors rhodopsin and opsin in native membranes. J Biol Chem 278(24):21655–21662. doi: 10.1074/jbc.M302536200 CrossRefGoogle Scholar
  33. 33.
    Ruprecht JJ, Mielke T, Vogel R, Villa C, Schertler GF (2004) Electron crystallography reveals the structure of metarhodopsin I. EMBO J 23(18):3609–3620. doi: 10.1038/sj.emboj.7600374 CrossRefGoogle Scholar
  34. 34.
    Periole X, Huber T, Marrink SJ, Sakmar TP (2007) G protein-coupled receptors self-assemble in dynamics simulations of model bilayers. J Am Chem Soc 129(33):10126–10132. doi: 10.1021/ja0706246 CrossRefGoogle Scholar
  35. 35.
    Simpson LM, Taddese B, Wall ID, Reynolds CA (2010) Bioinformatics and molecular modelling approaches to GPCR oligomerization. Curr Opin Pharmacol 10(1):30–37. doi: 10.1016/j.coph.2009.11.001 CrossRefGoogle Scholar
  36. 36.
    Periole X, Knepp AM, Sakmar TP, Marrink SJ, Huber T (2012) Structural determinants of the supramolecular organization of G protein-coupled receptors in bilayers. J Am Chem Soc 134(26):10959–10965. doi: 10.1021/ja303286e CrossRefGoogle Scholar
  37. 37.
    Rodriguez D, Gutierrez-de-Teran H (2012) Characterization of the homodimerization interface and functional hotspots of the CXCR4 chemokine receptor. Proteins 80(8):1919–1928. doi: 10.1002/prot.24099 Google Scholar
  38. 38.
    Prasanna X, Chattopadhyay A, Sengupta D (2014) Cholesterol modulates the dimer interface of the beta(2)-adrenergic receptor via cholesterol occupancy sites. Biophys J 106(6):1290–1300. doi: 10.1016/j.bpj.2014.02.002 CrossRefGoogle Scholar
  39. 39.
    Provasi D, Boz MB, Johnston JM, Filizola M (2015) Preferred supramolecular organization and dimer interfaces of opioid receptors from simulated self-association. PLoS Comput Biol 11(3):e1004148. doi: 10.1371/journal.pcbi.1004148 CrossRefGoogle Scholar
  40. 40.
    Johnston JM, Wang H, Provasi D, Filizola M (2012) Assessing the relative stability of dimer interfaces in g protein-coupled receptors. PLoS Comput Biol 8(8):e1002649. doi: 10.1371/journal.pcbi.1002649 CrossRefGoogle Scholar
  41. 41.
    Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The protein data bank. Nucleic Acids Res 28(1):235–242CrossRefGoogle Scholar
  42. 42.
    Krissinel E, Henrick K (2007) Inference of macromolecular assemblies from crystalline state. J Mol Biol 372(3):774–797. doi: 10.1016/j.jmb.2007.05.022 CrossRefGoogle Scholar
  43. 43.
    Xue L, Rovira X, Scholler P, Zhao H, Liu J, Pin JP, Rondard P (2015) Major ligand-induced rearrangement of the heptahelical domain interface in a GPCR dimer. Nat Chem Biol 11(2):134–140. doi: 10.1038/nchembio.1711 CrossRefGoogle Scholar
  44. 44.
    Schrödinger, LLC (2010) The PyMOL molecular graphics system, Version 1.7Google Scholar
  45. 45.
    Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14(1):33–38CrossRefGoogle Scholar
  46. 46.
    Eswar N, Webb B, Marti-Renom MA, Madhusudhan MS, Eramian D, Shen M-y, Pieper U, Sali A (2001) Comparative protein structure modeling using MODELLER. In: Coligan JE (ed) Current protocols in protein science, Wiley, Hoboken. doi: 10.1002/0471140864.ps0209s50
  47. 47.
    Consortium TU (2015) UniProt: a hub for protein information. Nucleic Acids Res 43(D1):D204–D212. doi: 10.1093/nar/gku989 CrossRefGoogle Scholar
  48. 48.
    Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R, Thompson JD, Gibson TJ, Higgins DG (2007) Clustal W and Clustal X version 2.0. Bioinformatics 23(21):2947–2948. doi: 10.1093/bioinformatics/btm404 CrossRefGoogle Scholar
  49. 49.
    Marrink SJ, Risselada HJ, Yefimov S, Tieleman DP, de Vries AH (2007) The MARTINI force field: coarse grained model for biomolecular simulations. J Phys Chem B 111(27):7812–7824. doi: 10.1021/jp071097f CrossRefGoogle Scholar
  50. 50.
    Monticelli L, Kandasamy SK, Periole X, Larson RG, Tieleman DP, Marrink S-J (2008) The MARTINI coarse-grained force field: extension to proteins. J Chem Theory Comput 4(5):819–834. doi: 10.1021/ct700324x CrossRefGoogle Scholar
  51. 51.
    Ghosh A, Sonavane U, Joshi R (2014) Multiscale modelling to understand the self-assembly mechanism of human beta2-adrenergic receptor in lipid bilayer. Comput Biol Chem 48:29–39. doi: 10.1016/j.compbiolchem.2013.11.002 CrossRefGoogle Scholar
  52. 52.
    Wassenaar TA, Ingólfsson HI, Böckmann RA, Tieleman DP, Marrink SJ (2015) Computational lipidomics with insane: a versatile tool for generating custom membranes for molecular simulations. J Chem Theory Comput 11(5):2144–2155. doi: 10.1021/acs.jctc.5b00209 CrossRefGoogle Scholar
  53. 53.
    Eargle J, Luthey-Schulten Z (2012) NetworkView: 3D display and analysis of protein.RNA interaction networks. Bioinformatics 28(22):3000–3001. doi: 10.1093/bioinformatics/bts546 CrossRefGoogle Scholar
  54. 54.
    Kabsch W, Sander C (1983) Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 22(12):2577–2637. doi: 10.1002/bip.360221211 CrossRefGoogle Scholar
  55. 55.
    Pronk S, Pall S, Schulz R, Larsson P, Bjelkmar P, Apostolov R, Shirts MR, Smith JC, Kasson PM, van der Spoel D, Hess B, Lindahl E (2013) GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics 29(7):845–854. doi: 10.1093/bioinformatics/btt055 CrossRefGoogle Scholar
  56. 56.
    Shih AY, Freddolino PL, Arkhipov A, Schulten K (2007) Assembly of lipoprotein particles revealed by coarse-grained molecular dynamics simulations. J Struct Biol 157(3):579–592. doi: 10.1016/j.jsb.2006.08.006 CrossRefGoogle Scholar
  57. 57.
    Shih AY, Freddolino PL, Sligar SG, Schulten K (2007) Disassembly of nanodiscs with cholate. Nano Lett 7(6):1692–1696. doi: 10.1021/nl0706906 CrossRefGoogle Scholar
  58. 58.
    Wassenaar TA, Pluhackova K, Bockmann RA, Marrink SJ, Tieleman DP (2014) Going backward: a flexible geometric approach to reverse transformation from coarse grained to atomistic models. J Chem Theory Comput 10(2):676–690. doi: 10.1021/ct400617g CrossRefGoogle Scholar
  59. 59.
    Brooks BR, Brooks CL 3rd, Mackerell AD Jr, Nilsson L, Petrella RJ, Roux B, Won Y, Archontis G, Bartels C, Boresch S, Caflisch A, Caves L, Cui Q, Dinner AR, Feig M, Fischer S, Gao J, Hodoscek M, Im W, Kuczera K, Lazaridis T, Ma J, Ovchinnikov V, Paci E, Pastor RW, Post CB, Pu JZ, Schaefer M, Tidor B, Venable RM, Woodcock HL, Wu X, Yang W, York DM, Karplus M (2009) CHARMM: the biomolecular simulation program. J Comput Chem 30(10):1545–1614. doi: 10.1002/jcc.21287 CrossRefGoogle Scholar
  60. 60.
    Lim JB, Rogaski B, Klauda JB (2012) Update of the cholesterol force field parameters in CHARMM. J Phys Chem B 116(1):203–210. doi: 10.1021/jp207925m CrossRefGoogle Scholar
  61. 61.
    Huang J, MacKerell AD Jr (2013) CHARMM36 all-atom additive protein force field: validation based on comparison to NMR data. J Comput Chem 34(25):2135–2145. doi: 10.1002/jcc.23354 CrossRefGoogle Scholar
  62. 62.
    Schlitter J, Engels M, Kruger P (1994) Targeted molecular dynamics: a new approach for searching pathways of conformational transitions. J Mol Graph 12(2):84–89CrossRefGoogle Scholar
  63. 63.
    Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, Chipot C, Skeel RD, Kale L, Schulten K (2005) Scalable molecular dynamics with NAMD. J Comput Chem 26(16):1781–1802. doi: 10.1002/jcc.20289 CrossRefGoogle Scholar
  64. 64.
    Castillo N, Monticelli L, Barnoud J, Tieleman DP (2013) Free energy of WALP23 dimer association in DMPC, DPPC, and DOPC bilayers. Chem Phys Lipids 169:95–105. doi: 10.1016/j.chemphyslip.2013.02.001 CrossRefGoogle Scholar
  65. 65.
    Glykos NM (2006) Software news and updates. Carma: a molecular dynamics analysis program. J Comput Chem 27(14):1765–1768. doi: 10.1002/jcc.20482 CrossRefGoogle Scholar
  66. 66.
    Hunter JD (2007) Matplotlib: a 2D graphics environment. Comput Sci Eng 9(3):90–95CrossRefGoogle Scholar
  67. 67.
    Eisenhaber F, Lijnzaad P, Argos P, Sander C, Scharf M (1995) The double cubic lattice method: efficient approaches to numerical integration of surface area and volume and to dot surface contouring of molecular assemblies. J Comput Chem 16(3):273–284. doi: 10.1002/jcc.540160303 CrossRefGoogle Scholar
  68. 68.
    Levy ED (2010) A simple definition of structural regions in proteins and its use in analyzing interface evolution. J Mol Biol 403(4):660–670. doi: 10.1016/j.jmb.2010.09.028 CrossRefGoogle Scholar
  69. 69.
    Chothia C (1976) The nature of the accessible and buried surfaces in proteins. J Mol Biol 105(1):1–12CrossRefGoogle Scholar
  70. 70.
    Miller S, Janin J, Lesk AM, Chothia C (1987) Interior and surface of monomeric proteins. J Mol Biol 196(3):641–656CrossRefGoogle Scholar
  71. 71.
    Guerois R, Nielsen JE, Serrano L (2002) Predicting changes in the stability of proteins and protein complexes: a study of more than 1000 mutations. J Mol Biol 320(2):369–387. doi: 10.1016/S0022-2836(02)00442-4 CrossRefGoogle Scholar
  72. 72.
    Schymkowitz J, Borg J, Stricher F, Nys R, Rousseau F, Serrano L (2005) The FoldX web server: an online force field. Nucleic Acids Res 33(Web Server issue):W382–W388. doi: 10.1093/nar/gki387 CrossRefGoogle Scholar
  73. 73.
    Anand P, Nagarajan D, Mukherjee S, Chandra N (2014) ABS-Scan: in silico alanine scanning mutagenesis for binding site residues in protein-ligand complex. F1000Research 3:214. doi: 10.12688/f1000research.5165.2 Google Scholar
  74. 74.
    Sethi A, Eargle J, Black AA, Luthey-Schulten Z (2009) Dynamical networks in tRNA:protein complexes. Proc Natl Acad Sci USA 106(16):6620–6625. doi: 10.1073/pnas.0810961106 CrossRefGoogle Scholar
  75. 75.
    Girvan M, Newman ME (2002) Community structure in social and biological networks. Proc Natl Acad Sci USA 99(12):7821–7826. doi: 10.1073/pnas.122653799 CrossRefGoogle Scholar
  76. 76.
    Salom D, Lodowski DT, Stenkamp RE, Le Trong I, Golczak M, Jastrzebska B, Harris T, Ballesteros JA, Palczewski K (2006) Crystal structure of a photoactivated deprotonated intermediate of rhodopsin. Proc Natl Acad Sci USA 103(44):16123–16128. doi: 10.1073/pnas.0608022103 CrossRefGoogle Scholar
  77. 77.
    Park JH, Scheerer P, Hofmann KP, Choe HW, Ernst OP (2008) Crystal structure of the ligand-free G-protein-coupled receptor opsin. Nature 454(7201):183–187. doi: 10.1038/nature07063 CrossRefGoogle Scholar
  78. 78.
    Huang J, Chen S, Zhang JJ, Huang XY (2013) Crystal structure of oligomeric beta1-adrenergic G protein-coupled receptors in ligand-free basal state. Nat Struct Mol Biol 20(4):419–425. doi: 10.1038/nsmb.2504 CrossRefGoogle Scholar
  79. 79.
    Murakami M, Kouyama T (2008) Crystal structure of squid rhodopsin. Nature 453(7193):363–367. doi: 10.1038/nature06925 CrossRefGoogle Scholar
  80. 80.
    Liu W, Chun E, Thompson AA, Chubukov P, Xu F, Katritch V, Han GW, Roth CB, Heitman LH, IJzerman AP, Cherezov V, Stevens RC (2012) Structural basis for allosteric regulation of GPCRs by sodium ions. Science 337(6091):232–236. doi: 10.1126/science.1219218 CrossRefGoogle Scholar
  81. 81.
    Wu B, Chien EY, Mol CD, Fenalti G, Liu W, Katritch V, Abagyan R, Brooun A, Wells P, Bi FC, Hamel DJ, Kuhn P, Handel TM, Cherezov V, Stevens RC (2010) Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 330(6007):1066–1071. doi: 10.1126/science.1194396 CrossRefGoogle Scholar
  82. 82.
    Mondal S, Johnston JM, Wang H, Khelashvili G, Filizola M, Weinstein H (2013) Membrane driven spatial organization of GPCRs. Sci Rep 3:2909. doi: 10.1038/srep02909 Google Scholar
  83. 83.
    Johnston JM, Filizola M (2014) Differential stability of the crystallographic interfaces of mu- and kappa-opioid receptors. PLoS ONE 9(2):e90694. doi: 10.1371/journal.pone.0090694 CrossRefGoogle Scholar
  84. 84.
    Nichols SE, Hernandez CX, Wang Y, McCammon JA (2013) Structure-based network analysis of an evolved G protein-coupled receptor homodimer interface. Protein Sci Publ Protein Soc 22(6):745–754. doi: 10.1002/pro.2258 CrossRefGoogle Scholar
  85. 85.
    Wang J, He L, Combs CA, Roderiquez G, Norcross MA (2006) Dimerization of CXCR4 in living malignant cells: control of cell migration by a synthetic peptide that reduces homologous CXCR4 interactions. Mol Cancer Ther 5(10):2474–2483. doi: 10.1158/1535-7163.MCT-05-0261 CrossRefGoogle Scholar
  86. 86.
    Cang X, Du Y, Mao Y, Wang Y, Yang H, Jiang H (2013) Mapping the functional binding sites of cholesterol in beta2-adrenergic receptor by long-time molecular dynamics simulations. J Phys Chem B 117(4):1085–1094. doi: 10.1021/jp3118192 CrossRefGoogle Scholar
  87. 87.
    Zheng H, Pearsall EA, Hurst DP, Zhang Y, Chu J, Zhou Y, Reggio PH, Loh HH, Law PY (2012) Palmitoylation and membrane cholesterol stabilize mu-opioid receptor homodimerization and G protein coupling. BMC cell biology 13:6. doi: 10.1186/1471-2121-13-6 CrossRefGoogle Scholar
  88. 88.
    Filizola M, Olmea O, Weinstein H (2002) Prediction of heterodimerization interfaces of G-protein coupled receptors with a new subtractive correlated mutation method. Protein Eng 15(11):881–885CrossRefGoogle Scholar
  89. 89.
    Kaczor AA, Guixà-González R, Carrió P, Poso A, Dove S, Pastor M, Selent J (2015) Multi-component protein–protein docking based protocol with external scoring for modeling dimers of G protein-coupled receptors. Mol Inf 34(4):246–255. doi: 10.1002/minf.201400088 CrossRefGoogle Scholar
  90. 90.
    Kota P, Reeves PJ, Rajbhandary UL, Khorana HG (2006) Opsin is present as dimers in COS1 cells: identification of amino acids at the dimeric interface. Proc Natl Acad Sci USA 103(9):3054–3059. doi: 10.1073/pnas.0510982103 CrossRefGoogle Scholar
  91. 91.
    Jastrzebska B, Chen Y, Orban T, Jin H, Hofmann L, Palczewski K (2015) Disruption of rhodopsin dimerization with synthetic peptides targeting an interaction interface. J Biol Chem 290(42):25728–25744. doi: 10.1074/jbc.M115.662684 CrossRefGoogle Scholar
  92. 92.
    Mondal S, Khelashvili G, Weinstein H (2014) Not just an oil slick: how the energetics of protein-membrane interactions impacts the function and organization of transmembrane proteins. Biophys J 106(11):2305–2316. doi: 10.1016/j.bpj.2014.04.032 CrossRefGoogle Scholar
  93. 93.
    Kunishima N, Shimada Y, Tsuji Y, Sato T, Yamamoto M, Kumasaka T, Nakanishi S, Jingami H, Morikawa K (2000) Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature 407(6807):971–977. doi: 10.1038/35039564 CrossRefGoogle Scholar
  94. 94.
    Rasmussen SG, DeVree BT, Zou Y, Kruse AC, Chung KY, Kobilka TS, Thian FS, Chae PS, Pardon E, Calinski D, Mathiesen JM, Shah ST, Lyons JA, Caffrey M, Gellman SH, Steyaert J, Skiniotis G, Weis WI, Sunahara RK, Kobilka BK (2011) Crystal structure of the beta2 adrenergic receptor-Gs protein complex. Nature 477(7366):549–555. doi: 10.1038/nature10361 CrossRefGoogle Scholar
  95. 95.
    Seibt BF, Schiedel AC, Thimm D, Hinz S, Sherbiny FF, Muller CE (2013) The second extracellular loop of GPCRs determines subtype-selectivity and controls efficacy as evidenced by loop exchange study at A2 adenosine receptors. Biochem Pharmacol 85(9):1317–1329. doi: 10.1016/j.bcp.2013.03.005 CrossRefGoogle Scholar
  96. 96.
    Tan Q, Zhu Y, Li J, Chen Z, Han GW, Kufareva I, Li T, Ma L, Fenalti G, Zhang W, Xie X, Yang H, Jiang H, Cherezov V, Liu H, Stevens RC, Zhao Q, Wu B (2013) Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex. Science 341(6152):1387–1390. doi: 10.1126/science.1241475 CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Fotis A. Baltoumas
    • 1
  • Margarita C. Theodoropoulou
    • 1
    • 2
  • Stavros J. Hamodrakas
    • 1
    Email author
  1. 1.Department of Cell Biology and Biophysics, Faculty of BiologyNational and Kapodistrian University of AthensAthensGreece
  2. 2.Department of Computer Science and Biomedical InformaticsUniversity of Central GreeceLamiaGreece

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