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Modeling GPCRs

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GPCRs: From Deorphanization to Lead Structure Identification

Part of the book series: Ernst Schering Foundation Symposium Proceedings ((SCHERING FOUND,volume 2006/2))

Abstract

Many GPCR models have been built over the years for many different purposes, of which drug-design undoubtedly has been the most frequent one. The release of the structure of bovine rhodopsin in August 2000 enabled us to analyze models built before that period to learn things for the models we build today. We conclude that the GPCR modeling field is riddled with “common knowledge”. Several characteristics of the bovine rhodopsin structure came as a big surprise, and had obviously not been predicted, which led to large errors in the models. Some of these surprises, however, could have been predicted if the modelers had more rigidly stuck to the rule that holds for all models, namely that a model should explain all experimental facts, and not just those facts that agree with the modeler's preconceptions.

In memoriam Antonio Paiva

While we were working on this article, our good friend, colleague, and mentor, Antonio Paiva, died after losing the fight to cancer. We know Antonio as a stimulating force in the GPCR field. He has been one of the founding fathers of the informal GPCR club that met regularly at the EMBL in the early 1990s. The GPCRDB sprouted from these meetings. The thousands of scientists that use the GPCRDB every day owe Antonio thanks. His co-authors will miss him, and send words of condolence to his family. May they find consolation in the fact that the cancer could not stop him from finishing this article. We will miss him.

In memoriam Florence Horn

This paper is a dedication to the memory of Florence Horn who died shortly after we finished this article. Flo did so much to make genomics data come alive in a way that was meaningful to her and to thousands of researchers in bioinformatics, molecular biology, structural biology, and medicinal chemistry. Along with all these researchers, the coauthors of this paper wish to put on record their thanks to Flo and to remember her as a colleague who bestowed her good humor and joie de vivre on all those who worked with her.

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References

  • Bairoch A, Apweiler R, Wu CH, Barker WC, Boeckmann B, Ferro S, Gasteiger E, Huang H, Lopez R, Magrane M, Martin MJ, Natale DA, O'Donovan C, Redaschi N, Yeh LS (2005) The universal protein resource (UniProt). Nucleic Acids Res 33:D154–D159

    Article  CAS  PubMed  Google Scholar 

  • Ballesteros JA, Weinstein H (1995) Integrated methods for modeling G-protein coupled receptors. Methods Neurosci 25:366–428

    Article  CAS  Google Scholar 

  • Ballesteros JA, Shi L, Javitch JA (2001) 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 60:1–19

    CAS  PubMed  Google Scholar 

  • Beukers MW, Kristiansen I, Ijzerman AP, Edvardsen O (1999) TinyGRAP data-base: a bioinformatics tool to mine G protein-coupled receptor mutant data. TiPS 1999 20:475–477

    CAS  Google Scholar 

  • Birney E, Clamp M, Durbin R (2004) GeneWise and Genomewise. Genome Res 14:988–995

    Article  CAS  PubMed  Google Scholar 

  • Bramblett RD, Panu AM, Ballesteros JA, Reggio PH (1995) Construction of a 3D model of the cannabinoid CB1 receptor: determination of helix ends and helix orientation. Life Sci 56:1971–1982

    Article  CAS  PubMed  Google Scholar 

  • Bywater RP (2005) Location and nature of the residues important for ligand recognition in G Protein-coupled receptors. J Mol Recognit 18:60–72

    Article  CAS  PubMed  Google Scholar 

  • Campagne F, Bettler E, Vriend G, Weinstein H (2003) Batch mode generation of residue-based diagrams of proteins. Bioinformatics 19:1854–1855

    Article  CAS  PubMed  Google Scholar 

  • Chung DA, Zuiderweg ER, Fowler CB, Soyer OS, Mosberg HI, Neubig RR (2002) NMR structure of the second intracellular loop of the alpha 2A adrenergic receptor: evidence for a novel cytoplasmic helix. Biochemistry 41:3596–3604

    Article  CAS  PubMed  Google Scholar 

  • Church WB, Jones KA, Kuiper DA, Shine J, Iismaa TP (2002) Molecular modelling and site-directed mutagenesis of human GALR1 galanin receptor defines determinants of receptor subtype specificity. Protein Eng 5:313–323

    Article  Google Scholar 

  • Cochrane G, Adelbert P, Althorpe N et al. (2006) EMBL Nucleotide Sequence Database: developments in 2005. Nucleic Acids Res 34:D10–D15

    Article  CAS  PubMed  Google Scholar 

  • Cronet P, Sander C, Vriend G (1993) Modelling of transmembrane seven helix bundles. Protein Eng 6:59–64

    Article  CAS  PubMed  Google Scholar 

  • Donnelly D, Overington JP, Ruffle SV, Nugent JH, Blundell TL (1993) Modelling alpha-helical transmembrane domains: the calculation and use of substitution tables for lipid-facing residues. Protein Sci 2:55–70

    CAS  PubMed  Google Scholar 

  • Filizola M, Perez JJ, Carteni-Farina M (1998) BUNDLE: a program for building the transmembrane domains of G protein-coupled receptors. J Comput Aided Mol Des 12:111–118

    Article  CAS  PubMed  Google Scholar 

  • Gether U, Kobilka BK (1998) G Protein receptor activation: II. Mechanism of agonist activation. J Biol Chem 273:17979–17982

    Article  CAS  PubMed  Google Scholar 

  • Gouldson PR, Kidley NJ, Bywater RP, Psaroudakis G, Brooks HD, Diaz C, Shire D, Reynolds CA (2004) Toward the active conformations of rhodopsin and beta-2-adrenergic receptor. Proteins 56:67–84

    Article  CAS  PubMed  Google Scholar 

  • Henderson R, Schertler GFX (1990) The structure of bacteriorhodopsin and its relevance to the visual opsins and other seven-helix G protein-coupled receptors. Philos Trans R Soc Lond B Biol Sci 326:379–389

    Article  CAS  PubMed  Google Scholar 

  • Herzyk P, Hubbard RE (1998) Combined biophysical and biochemical information confirms arrangement of transmembrane helices visible from the three-dimensional map of frog rhodopsin. J Mol Biol 281:741–754

    Article  CAS  PubMed  Google Scholar 

  • Horn F, Weare J, Beukers MW, Horsch S, Bairoch A, Chen W, Edvardsen O, Campagne F, Vriend G (1998) GPCRDB: an information system for G protein-coupled receptors. Nucleic Acids Res 26:275–279

    Article  CAS  PubMed  Google Scholar 

  • Horn F, Bettler E, Oliveira L, Campagne F, Cohen FE, Vriend G (2003) GPCRDB information system for G protein-coupled receptors. Nucleic Acids Res 31:294–297

    Article  CAS  PubMed  Google Scholar 

  • Horn F, Lau AL, Cohen FE (2004) Automated extraction of mutation data from the literature: application of MuteXt to G protein-coupled receptors and nuclear hormone receptors. Bioinformatics 20:557–568

    Article  CAS  PubMed  Google Scholar 

  • Javitch JA, Ballesteros JA, Weinstein H, Chen J (1998) A cluster of aromatic residues in the sixth membrane-spanning segment of the D2 receptor is accessible to the binding-site crevice. Biochemistry 37:998–1006

    Article  CAS  PubMed  Google Scholar 

  • Johansson K (1999) Bioinformatics practical. http://alpha2.bmc.uu.se/~kenth/bioinfo/structure/secondary/08.html. Cited 24 November 2006

    Google Scholar 

  • Kuipers W, Van Wijngaarden I, Ijzerman AP (1994) A model of the serotonin 5-HT1A receptor: agonist and antagonist binding sites. Drug Des Discov 11:231–249

    CAS  PubMed  Google Scholar 

  • Kuipers W, Oliveira L, Paiva ACM, Rippmann F, Sander C, Vriend G, Ijzerman AP (1996) Sequence-function correlation in G protein-coupled receptors. In: Findlay JBC (ed) Membrane protein models. BIOS Scientific, Oxford

    Google Scholar 

  • Kuipers W, Oliveira L, Vriend G, IJzerman AP (1997) Identification of class-determining residues in G protein-coupled receptors by sequence analysis. Receptors Channels 5:159–174

    CAS  PubMed  Google Scholar 

  • Lequin O, Bolbach G, Frank F, Convert O, Girault-Lagrange S, Chassaing G, Lavielle S, Sagan S (2002) Involvement of the second extracellular loop (E2) of the neurokinin-1 receptor in the binding of substance P. Photoaffinity labeling and modeling studies. J Biol Chem 277:22386–22394

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Rodriguez ML, Murcia M, Benhamu B, Olivella M, Campillo M, Pardo L (2001) Computational model of the complex between GR113808 and the 5-HT4 receptor guided by site-directed mutagenesis and the crystal structure of rhodopsin. J Comput Aided Mol Des 15:1025–1033

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Rodriguez ML, Vicente B, Deupi X, Barrondo S, Olivella M, Morcillo MJ, Behamu B, Ballesteros JA, Salles J, Pardo L (2002) Design, synthesis and pharmacological evaluation of 5-hydroxytryptamine(1a) receptor ligands to explore the three-dimensional structure of the receptor. Mol Pharmacol 62:15–21

    Article  CAS  PubMed  Google Scholar 

  • Luecke H, Richter HT, Lanyi JK (1998) Proton transfer pathways in bacteriorhodopsin at 2.3 angstrom resolution. Science 280:1934–1937

    Article  CAS  PubMed  Google Scholar 

  • Mehler EL, Periole X, Hassan SA, Weinstein H (2002) Key issues in the computational simulation of GPCR function: representation of loop domains. J Comput Aided Mol Des 16:841–853

    Article  CAS  PubMed  Google Scholar 

  • Oliveira L, Paiva ACM, Vriend G (1993) A common motif in G protein-coupled seven transmembrane helix receptors. J Comput Aided Mol Des 7:649–658

    Article  CAS  Google Scholar 

  • Oliveira L, Paiva ACM, Vriend G (1999) A low resolution model for the interaction of G proteins with G protein-coupled receptors. Prot Eng 12:1087–1095

    Article  CAS  Google Scholar 

  • Oliveira L, Paiva PB, Paiva AC, Vriend G (2003a) Identification of functionally conserved residues with the use of entropy-variability plots. Proteins 52:544–552

    Article  CAS  PubMed  Google Scholar 

  • Oliveira L, Paiva PB, Paiva AC, Vriend G (2003b) Sequence analysis reveals how G protein-coupled receptors transduce the signal to the G protein. Proteins 52:553–560

    Article  CAS  PubMed  Google Scholar 

  • Orry AJW, Wallace BA (2000) Modelling and docking the endothelin G protein-coupled receptor. Biophys J 79:3083:3094

    Article  CAS  PubMed  Google Scholar 

  • 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 289:739–745

    Article  CAS  PubMed  Google Scholar 

  • Pardo L, Ballesteros JA, Osman R, Weinstein H (1992) On the use of the transmembrane domain of bacteriorhodopsin as a template for modeling the three-dimensional structure of guanine nucleotide-binding regulatory protein-coupled receptors. PNAS 89:4009-4012

    Article  CAS  PubMed  Google Scholar 

  • Pebay-Peyroula E, Rummel G, Rosenbusch JP, Landau EM (1997) X-ray structure of bacteriorhodopsin at 2.5 angstroms from microcrystals grown in lipid cubic phases. Science 277:1676–1681

    Article  CAS  PubMed  Google Scholar 

  • Pellegrini M, Bremer AA, Ulfers AL, Boyd ND, Mierke DF (2001) Molecular characterization of the substance P*neurokinin-1 receptor complex: development of an experimentally based model. J Biol Chem 276:22862–22867

    Article  CAS  PubMed  Google Scholar 

  • Pogozheva ID, Lomize AL, Mosberg HI (1997) The transmembrane 7-alpha-bundle of rhodopsin: distance geometry calculations with hydrogen bonding constraints. Biophys J 72:1963–1985

    Article  CAS  PubMed  Google Scholar 

  • Protein Structure Prediction Center (2006) http://predictioncenter.gc.ucdavis.edu/. Cited 24 November 2006

    Google Scholar 

  • Prusis P, Schiöth HB, Muceniece R, Herzyk P, Afshar M, Hubbard RE, Wikberg JES (1997) Modelling of the three-dimensional structure of the human melanocortin 1 receptor, using an automated method and docking of a rigid cyclic melanocyte stimulating hormone core peptide. J Mol Graph Model 15:307–315

    Article  CAS  PubMed  Google Scholar 

  • Rippmann F, Bottcher E (1993) Molecular modelling of serotonin receptors. 7TM 3:1–27

    Google Scholar 

  • Schadel SA, Heck M, Maretzki D, Filipek S, Teller DC, Palczewski K, Hofmann KP (2003) Ligand channeling within a G-protein-coupled receptor. The entry and exit of retinals in native opsin. J Biol Chem 278:24896–24903

    Article  PubMed  Google Scholar 

  • Schertler GF (2005) Structure of rhodopsin and the metarhodopsin I photointermediate. Curr Opin Struct Biol 15:408–415

    Article  CAS  PubMed  Google Scholar 

  • Schertler GFX, Hargrave PA (1995) Projection structure of frog rhodopsin in two crystal forms. PNAS 192:11578–11582

    Article  Google Scholar 

  • Schertler GF, Villa C, Henderson R (1993) Projection structure of rhodopsin. Nature 362:770–772

    Article  CAS  PubMed  Google Scholar 

  • Shi L, Javitch JA (2002) The binding site of aminergic G protein-coupled receptors: the transmembrane segments and second extracellular loop. Annu Rev Pharmacol Toxicol 42:437–467

    Article  CAS  PubMed  Google Scholar 

  • Shim JY, Welsh WJ, Howlett AC (2003) Homology model of the CB1 cannabinoid receptor: sites critical for nonclassical cannabinoid agonist interaction. Biopolymers 71:169–189

    Article  CAS  PubMed  Google Scholar 

  • Szundi I, Ruprecht JJ, Epps J, Villa C, Swartz TE, Lewis JW, Schertler GF, Kliger DS (2006) Rhodopsin photointermediates in two-dimensional crystals at physiological temperatures. Biochemistry 45:4974–4982

    Article  CAS  PubMed  Google Scholar 

  • Takeda K, Sato H, Hino T, Kono M, Fukuda K, Sakurai I, Okada T, Kouyama T (1998) A novel three-dimensional crystal of bacteriorhodopsin obtained by successive fusion of the vesicular assemblies. J Mol Biol 283:463–474

    Article  CAS  PubMed  Google Scholar 

  • Teller DC, Okada T, Behnke CA, Palczewski K, Stenkamp RE (2001) Advances in determination of a high-resolution three-dimensional structure of rhodopsin, a model of G protein-coupled receptors. Biochemistry 40:7761–7772

    Article  CAS  PubMed  Google Scholar 

  • Unger VM, Schertler GFX (1995) Low resolution structure of bovine rhodopsin determined by electron cryo-microscopy. Biophys J 68:1776–1786

    Article  CAS  PubMed  Google Scholar 

  • Unger VM, Hargrave PA, Baldwin JM, Schertler GFX (1997) Arrangement of rhodopsin transmembrane alpha-helices. Nature 389:203–206

    Article  CAS  PubMed  Google Scholar 

  • Vaidehi N, Floriano WB, Trabanino R, Hall SE, Freddolino P, Choi EJ, Zamanakos G, Goddard WA 3rd (2002) Prediction of structure and function of G protein-coupled receptors. PNAS 2002 99:12622–12627

    Article  CAS  Google Scholar 

  • Venclovas C, Zemla A, Fidelis K, Moult J (2001) Comparison of performance in successive CASP experiments. Proteins Suppl 5:163–170

    Article  Google Scholar 

  • Vriend G (1990) WHAT IF: a molecular modeling and drug design program. J Mol Graph 8:52–56

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Asenjo AB, Oprian DD (1993) Identification of the Cl-binding site in the human red and green colour vision pigments. Biochemistry 32:2125–2130

    Article  CAS  PubMed  Google Scholar 

  • Watson S, Arkinstall S. The G-protein linked receptor Facts Book. 1994, Academic Press Ltd, ISBN 0-12-738440-5

    Google Scholar 

  • Yang X, Wang Z, Dong W, Ling L, Yang H, Chen R (2003) Modeling and docking of the three-dimensional structure of the human melanocortin 4 receptor. J Protein Chem 22:335–344

    Article  CAS  PubMed  Google Scholar 

  • Yeagle PL, Alderfer JL, Albert AD (1995) Structure of the third cytoplasmic loop of bovine rhodopsin. Biochemistry 34:14621–14625

    Article  CAS  PubMed  Google Scholar 

  • Yeagle PL, Alderfer JL, Albert AD (1996) Structure determination of the fourth cytoplasmic loop and carboxyl terminal domain of bovine rhodopsin. Mol Vis 2:12–19

    CAS  PubMed  Google Scholar 

  • Yeagle PL, Alderfer JL, Salloum AC, Ali L, Albert AD (1997) The first and second cytoplasmic loops of the G protein-receptor, rhodopsin, independently form betaturns. Biochemistry 36:3864–3869

    Article  CAS  PubMed  Google Scholar 

  • Yeagle PL, Salloum A, Chopra A, Bhawsar N, Ali L, Kuzmanovski G, Alderfer JL, Albert AD (2000) Structures of the intradiskal loops and amino terminus of the G-protein receptor, rhodopsin. J Pept Res 55:455–465

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The GPCRDB was initiated as an EC sponsored project (PL 950224). GV acknowledges financial support from BioRange and BioSapiens. The BioSapiens project is funded by the European Commission within its FP6 Programme, under the thematic area “Life sciences, genomics and biotechnology for health,” contract number LSHG-CT-2003–503265. BioRange is a programme of the Netherlands Bioinformatics Centre (NBIC), which is supported by a BSIK grant through the Netherlands Genomics Initiative (NGI).

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Authors and Affiliations

  1. Escola Paulista de Medicina, Sao Paulo, Brazil

    A. C. M. Paiva† & L. Oliveira

  2. Laboratoire de Biologie, Informatique et Math\'ematiques, CEA, Grenoble, France

    F. Horn†

  3. Magdalen College, OX1 4AU, Oxford, England

    R. P. Bywater

  4. CMBI NCMLS, UMC, Geert Grooteplein 28, 6525, GA Nijmegen, The Netherlands

    G. Vriend

Authors
  1. A. C. M. Paiva†
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  2. L. Oliveira
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  3. F. Horn†
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  4. R. P. Bywater
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  5. G. Vriend
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Corresponding author

Correspondence to G. Vriend .

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H. Bourne R. Horuk J. Kuhnke H. Michel

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© 2007 Springer-Verlag

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Paiva†, A.C.M., Oliveira, L., Horn†, F., Bywater, R.P., Vriend, G. (2007). Modeling GPCRs. In: Bourne, H., Horuk, R., Kuhnke, J., Michel, H. (eds) GPCRs: From Deorphanization to Lead Structure Identification. Ernst Schering Foundation Symposium Proceedings, vol 2006/2. Springer, Berlin, Heidelberg. https://doi.org/10.1007/2789_2006_002

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