Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The GPCR Network: a large-scale collaboration to determine human GPCR structure and function

Nature Reviews Drug Discovery volume 12, pages 25–34 (2013)Cite this article

Subjects

Abstract

G protein-coupled receptors (GPCRs) are targeted by ∼30–40% of marketed drugs, and their key roles in normal physiology and in disease demonstrate that an understanding of their structure and function is valuable to researchers in both basic science and drug discovery. However, until recently, detailed structural information on this protein family was limited by challenges in X-ray crystallographic analysis of such membrane proteins. The GPCR Network was created in 2010 with the goal of structurally characterizing 15–25 representative human GPCRs within 5 years, based on an active outreach programme addressing an interdisciplinary community of scientists interested in GPCR structure, chemistry and biology. Here, we provide an overview of how this collaborative effort has enabled the structural determination and characterization of eight human GPCRs so far, and discuss some of the challenges that remain in gaining more detailed insights into structure–function relationships in this receptor superfamily.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Phylogenetic tree representation of the human GPCR superfamily.
Figure 2: The strategy of the GPCR Network.
Figure 3: Community-wide predictions of GPCR–ligand docking and receptor interactions.
Figure 4: Receptor diversity in class A GPCRs.

References

  1. Rajagopal, S., Rajagopal, K. & Lefkowitz, R. J. Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nature Rev. Drug Discov. 9, 373–386 (2010).

    Article  CAS  Google Scholar 

  2. Wise, A., Gearing, K. & Rees, S. Target validation of G-protein coupled receptors. Drug Discov. Today 7, 235–246 (2002).

    Article  CAS  Google Scholar 

  3. Kobilka, B. K. & Deupi, X. Conformational complexity of G-protein-coupled receptors. Trends Pharmacol. Sci. 28, 397–406 (2007).

    Article  CAS  Google Scholar 

  4. Cherezov, V. et al. High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor. Science 318, 1258–1265 (2007).

    Article  CAS  Google Scholar 

  5. Jaakola, V. P. et al. The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science 322, 1211–1217 (2008).

    Article  CAS  Google Scholar 

  6. Weigelt, J., McBroom-Cerajewski, L. D., Schapira, M., Zhao, Y. & Arrowsmith, C. H. Structural genomics and drug discovery: all in the family. Curr. Opin. Chem. Biol. 12, 32–39 (2008).

    Article  CAS  Google Scholar 

  7. Mileni, M. et al. Structure-guided inhibitor design for human FAAH by interspecies active site conversion. Proc. Natl Acad. Sci. USA 105, 12820–12824 (2008).

    Article  CAS  Google Scholar 

  8. Oksenberg, D. et al. A single amino-acid difference confers major pharmacological variation between human and rodent 5-HT1B receptors. Nature 360, 161–163 (1992).

    Article  CAS  Google Scholar 

  9. Tucker, A. L. et al. A1 adenosine receptors. Two amino acids are responsible for species differences in ligand recognition. J. Biol. Chem. 269, 27900–27906 (1994).

    CAS  PubMed  Google Scholar 

  10. Yao, B. B. et al. Molecular modeling and pharmacological analysis of species-related histamine H3 receptor heterogeneity. Neuropharmacology 44, 773–786 (2003).

    Article  CAS  Google Scholar 

  11. Valant, C., Robert Lane, J., Sexton, P. M. & Christopoulos, A. The best of both worlds? Bitopic orthosteric/allosteric ligands of G protein-coupled receptors. Annu. Rev. Pharmacol. Toxicol. 52, 153–178 (2012).

    Article  CAS  Google Scholar 

  12. Reynolds, K., Abagyan, R. & Katritch, V. in GPCR Molecular Pharmacology and Drug Targeting: Shifting Paradigms and New Directions (ed. Gilchrist, A. ) 385–433 (Wiley & Sons, 2010).

    Book  Google Scholar 

  13. Yarnitzky, T., Levit, A. & Niv, M. Y. Homology modeling of G-protein-coupled receptors with X-ray structures on the rise. Curr. Opin. Drug Discov. Devel. 13, 317–325 (2010).

    CAS  PubMed  Google Scholar 

  14. Cavasotto, C. N. & Phatak, S. S. Homology modeling in drug discovery: current trends and applications. Drug Discov. Today 14, 676–683 (2009).

    Article  CAS  Google Scholar 

  15. Michino, M. et al. Community-wide assessment of GPCR structure modelling and ligand docking: GPCR Dock 2008. Nature Rev. Drug Discov. 8, 455–463 (2009).

    Article  CAS  Google Scholar 

  16. Kufareva, I., Rueda, M., Katritch, V., Stevens, R. C. & Abagyan, R. Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment. Structure 19, 1108–1126 (2011).

    Article  CAS  Google Scholar 

  17. Thompson, A. A. et al. Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic. Nature 485, 395–399 (2012).

    Article  CAS  Google Scholar 

  18. Xu, F. et al. Structure of an agonist-bound human A2A adenosine receptor. Science 332, 322–327 (2011).

    Article  CAS  Google Scholar 

  19. Jaakola, V. P. et al. Ligand binding and subtype selectivity of the human A2A adenosine receptor: identification and characterization of essential amino acid residues. J. Biol. Chem. 285, 13032–13044 (2010).

    Article  CAS  Google Scholar 

  20. Deflorian, F. et al. Evaluation of molecular modeling of agonist binding in light of the crystallographic structure of an agonist-bound A2A adenosine receptor. J. Med. Chem. 55, 538–552 (2012).

    Article  CAS  Google Scholar 

  21. Tosh, D. K. et al. Optimization of adenosine 5′-carboxamide derivatives as adenosine receptor agonists using structure-based ligand design and fragment screening. J. Med. Chem. 55, 4297–4308 (2012).

    Article  CAS  Google Scholar 

  22. Wu, H. et al. Structure of the human κ-opioid receptor in complex with JDTic. Nature 485, 327–332 (2012).

    Article  CAS  Google Scholar 

  23. Wu, B. et al. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 330, 1066–1071 (2010).

    Article  CAS  Google Scholar 

  24. Chien, E. Y. et al. Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science 330, 1091–1095 (2010).

    Article  CAS  Google Scholar 

  25. Shimamura, T. et al. Structure of the human histamine H1 receptor complex with doxepin. Nature 475, 65–70 (2011).

    Article  CAS  Google Scholar 

  26. Hanson, M. A. et al. Crystal structure of a lipid G protein-coupled receptor. Science 335, 851–855 (2012).

    Article  CAS  Google Scholar 

  27. West, G. M. et al. Ligand-dependent perturbation of the conformational ensemble for the GPCR β2 adrenergic receptor revealed by HDX. Structure 19, 1424–1432 (2011).

    Article  CAS  Google Scholar 

  28. Palczewski, K. et al. Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289, 739–745 (2000).

    Article  CAS  Google Scholar 

  29. Murakami, M. & Kouyama, T. Crystal structure of squid rhodopsin. Nature 453, 363–367 (2008).

    Article  CAS  Google Scholar 

  30. Warne, T. et al. Structure of a β1-adrenergic G-protein-coupled receptor. Nature 454, 486–491 (2008).

    Article  CAS  Google Scholar 

  31. Haga, K. et al. Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist. Nature 482, 547–551 (2012).

    Article  CAS  Google Scholar 

  32. Kruse, A. C. et al. Structure and dynamics of the M3 muscarinic acetylcholine receptor. Nature 482, 552–556 (2012).

    Article  CAS  Google Scholar 

  33. Manglik, A. et al. Crystal structure of the μ-opioid receptor bound to a morphinan antagonist. Nature 485, 321–326 (2012).

    Article  CAS  Google Scholar 

  34. Granier, S. et al. Structure of the δ opioid receptor bound to naltrindole. Nature 485, 400–404 (2012).

    Article  CAS  Google Scholar 

  35. White, J. F. et al. Structure of the agonist-bound neurotensin receptor. Nature 490, 508–513 (2012).

    Article  CAS  Google Scholar 

  36. Standfuss, J. et al. The structural basis of agonist-induced activation in constitutively active rhodopsin. Nature 471, 656–660 (2011).

    Article  CAS  Google Scholar 

  37. Scheerer, P. et al. Crystal structure of opsin in its G-protein-interacting conformation. Nature 455, 497–502 (2008).

    Article  CAS  Google Scholar 

  38. Rosenbaum, D. M. et al. GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function. Science 318, 1266–1273 (2007).

    Article  CAS  Google Scholar 

  39. Rasmussen, S. G. et al. Structure of a nanobody-stabilized active state of the β2 adrenoceptor. Nature 469, 175–180 (2011).

    Article  CAS  Google Scholar 

  40. Hanson, M. A. et al. A specific cholesterol binding site is established by the 2.8 Å structure of the human β2-adrenergic receptor. Structure 16, 897–905 (2008).

    Article  CAS  Google Scholar 

  41. Wacker, D. et al. Conserved binding mode of human β2 adrenergic receptor inverse agonists and antagonist revealed by X-ray crystallography. J. Am. Chem. Soc. 132, 11443–11445 (2010).

    Article  CAS  Google Scholar 

  42. Lebon, G. et al. Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation. Nature 474, 521–525 (2011).

    Article  CAS  Google Scholar 

  43. Dore, A. S. et al. Structure of the adenosine A2A receptor in complex with ZM241385 and the xanthines XAC and caffeine. Structure 19, 1283–1293 (2011).

    Article  CAS  Google Scholar 

  44. Rasmussen, S. G. et al. Crystal structure of the β2 adrenergic receptor–Gs protein complex. Nature 477, 549–555 (2011).

    Article  CAS  Google Scholar 

  45. Katritch, V., Cherezov, V. & Stevens, R. C. Diversity and modularity of G protein-coupled receptor structures. Trends Pharmacol. Sci. 33, 17–27 (2012).

    Article  CAS  Google Scholar 

  46. Liu, J. J., Horst, R., Katritch, V., Stevens, R. C. & Wuthrich, K. Biased signaling pathways in β2-adrenergic receptor characterized by 19F-NMR. Science 335, 1106–1110 (2012).

    Article  CAS  Google Scholar 

  47. Johnston, J. M. & Filizola, M. Showcasing modern molecular dynamics simulations of membrane proteins through G protein-coupled receptors. Curr. Opin. Struct. Biol. 21, 552–558 (2011).

    Article  CAS  Google Scholar 

  48. Carlsson, J. et al. Structure-based discovery of A2A adenosine receptor ligands. J. Med. Chem. 53, 3748–3755 (2010).

    Article  CAS  Google Scholar 

  49. Katritch, V. et al. Structure-based discovery of novel chemotypes for adenosine A2A receptor antagonists. J. Med. Chem. 53, 1799–1809 (2010).

    Article  CAS  Google Scholar 

  50. Mysinger, M. M. et al. Structure-based ligand discovery for the protein–protein interface of chemokine receptor CXCR4. Proc. Natl Acad. Sci. USA 109, 5517–5522 (2012).

    Article  CAS  Google Scholar 

  51. Carlsson, J. et al. Ligand discovery from a dopamine D3 receptor homology model and crystal structure. Nature Chem. Biol. 7, 769–778 (2011).

    Article  CAS  Google Scholar 

  52. de Graaf, C. et al. Crystal structure-based virtual screening for fragment-like ligands of the human histamine H1 receptor. J. Med. Chem. 54, 8195–8206 (2011).

    Article  CAS  Google Scholar 

  53. Congreve, M., Langmead, C. & Marshall, F. H. The use of GPCR structures in drug design. Adv. Pharmacol. 62, 1–36 (2011).

    Article  CAS  Google Scholar 

  54. Shoichet, B. K. & Kobilka, B. K. Structure-based drug screening for G-protein-coupled receptors. Trends Pharmacol. Sci. 33, 268–272 (2012).

    Article  CAS  Google Scholar 

  55. Roth, C. B., Hanson, M. A. & Stevens, R. C. Stabilization of the human beta2-adrenergic receptor TM4–TM3–TM5 helix interface by mutagenesis of Glu122(3.41), a critical residue in GPCR structure. J. Mol. Biol. 376, 1305–1319 (2008).

    Article  CAS  Google Scholar 

  56. Xu, F., Liu, W., Hanson, M. A., Stevens, R. C. & Cherezov, V. Development of an automated high throughput LCP-FRAP assay to guide membrane protein crystallization in lipid mesophases. Cryst. Growth Des. 11, 1193–1201 (2011).

    Article  CAS  Google Scholar 

  57. Caffrey, M. & Cherezov, V. Crystallizing membrane proteins using lipidic mesophases. Nature Protoc. 4, 706–731 (2009).

    Article  CAS  Google Scholar 

  58. Fredriksson, R., Lagerstrom, M. C., Lundin, L. G. & Schioth, H. B. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol. Pharmacol. 63, 1256–1272 (2003).

    Article  CAS  Google Scholar 

  59. Katritch, V. et al. Analysis of full and partial agonists binding to β2-adrenergic receptor suggests a role of transmembrane helix V in agonist-specific conformational changes. J. Mol. Recognit. 22, 307–318 (2009).

    Article  CAS  Google Scholar 

  60. Katritch, V., Kufareva, I. & Abagyan, R. Structure based prediction of subtype-selectivity for adenosine receptor antagonists. Neuropharmacology 60, 108–115 (2011).

    Article  CAS  Google Scholar 

  61. Liu, W. et al. Structural basis for allosteric regulation of GPCRs by sodium ions. Science 337, 232–236 (2012).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The GPCR Network acknowledges support from the US National Institutes of Health (NIH)/National Institute of General Medical Sciences (NIGMS) PSI:Biology grant U54 GM094618 and the NIH Common Fund grant P50 GM073197 to the Joint Center for Innovative Membrane Protein Technologies (JCIMPT) for technology development. The authors are grateful to the members of the Scientific Advisory Board (T. W. Schwarz, B. L. Roth, R. M. Stroud, G. Wagner, S. H. White and I. A. Wilson) and community collaborators, including A. Brooun, G. Calo. R. Guerrini, T. Handel, M. Hanson, A. IJzerman, S. Iwata, K. Jacobson, J. Javitch, T. Kobayashi, B. Kobilka, P. D. Mosier, A. H. Newman, B. L. Roth, L. Shi and P. Wells. The authors thank K. Kadyshevskaya and I. Kufareva for assistance with figure preparation, and E. Abola and A. Walker for assistance with manuscript preparation.

Author information

Authors and Affiliations

  1. Vadim Cherezov and Vsevolod Katritch are at the Department of Molecular Biology, Raymond C. Stevens, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.,

    Raymond C. Stevens, Vadim Cherezov & Vsevolod Katritch

  2. Ruben Abagyan is at the University of California San Diego (UCSD) Skaggs School of Pharmacy and Pharmaceutical Sciences and at the San Diego Supercomputer Center, La Jolla, California 92093, USA.,

    Ruben Abagyan

  3. Peter Kuhn is at the Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.,

    Peter Kuhn

  4. Hugh Rosen is at the Department of Chemical Physiology and at the The Scripps Research Institute Molecular Screening Center, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.,

    Hugh Rosen

  5. Kurt Wüthrich is at the Department of Molecular Biology and at the Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.,

    Kurt Wüthrich

Authors
  1. Raymond C. Stevens
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vadim Cherezov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vsevolod Katritch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ruben Abagyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter Kuhn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hugh Rosen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kurt Wüthrich
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raymond C. Stevens.

Ethics declarations

Competing interests

R.C.S. is a founder, and H.R. is a founder and on the scientific advisory board, of Receptos, a GPCR structure-based drug discovery company. All other authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Community Nominated Targets programme

GPCR Network

IUPHAR database

JCIMPT Home Page

NIGMS PSI:Biology programme

Protein Data Bank

UniProt database

Glossary

Allosteric ligands

Ligands that bind elsewhere from the orthosteric binding site and influence the functional properties of the receptor. In some classifications, the intracellular binding partners (for example, G proteins) are considered to be allosteric molecules as they bind at a distance of 30 Å from the orthosteric ligand-binding site.

Bitopic ligands

Ligands that have both orthosteric ligand-binding properties as well as a secondary element that is able to bind to a neighbouring allosteric site on the receptor.

Cα atoms

The chiral carbon atoms to which the primary amine, the carboxylic group and the side chain are attached to in an amino acid. Comparison of three-dimensional structures of proteins is sometimes carried out by superimposing the Cα atoms of proteins, as this provides a simple estimate of the similarity of their skeleton or backbone structure.

Electron paramagnetic resonance

(EPR). Similar in concept to NMR spectroscopy, but whereas NMR examines the spins of atomic nuclei, EPR detects the spins of unpaired electrons.

Hydrogen–deuterium exchange mass spectroscopy

(HDX-MS). A technique used to probe protein conformations. The exchange rate of an amide hydrogen is substantially influenced by hydrogen bonding, and the exchange kinetics of an amide hydrogen can be highly reflective of its locations in secondary and tertiary structures.

Non-olfactory receptors

G protein-coupled receptors from the Rhodopsin family, excluding the ∼388 olfactory receptors.

Orthosteric ligands

Ligands that bind to the natural ligand-binding site on the receptor and thus directly compete with this natural ligand for receptor binding. For class A G protein-coupled receptors (GPCRs), the orthosteric binding site is typically in the cavity positioned in the extracellular portion of the seven-transmembrane region. For class B and class C GPCRs, pockets in this location are considered to be allosteric because their natural ligands bind in a separate extracellular domain.

Root mean square deviation

(RMSD). A quantitative measure of the similarity between two superimposed sets of atomic coordinates. RMSD values (units of Å) can be calculated for any type and subset of atoms: for example, for chiral carbon (Cα) atoms of proteins (Cα RMSD) for all residues; for residues in the transmembrane helices or the loops; as well as for non-hydrogen atoms of small-molecule ligands (ligand RMSD).

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Stevens, R., Cherezov, V., Katritch, V. et al. The GPCR Network: a large-scale collaboration to determine human GPCR structure and function. Nat Rev Drug Discov 12, 25–34 (2013). https://doi.org/10.1038/nrd3859

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd3859

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research