Opinion | Published:

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

Nature Reviews Drug Discovery volume 12, pages 2534 (2013) | Download Citation

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.

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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

Affiliations

  1. Raymond C. Stevens, Vadim Cherezov and Vsevolod Katritch are at the Department of Molecular Biology, 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

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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.

Corresponding author

Correspondence to Raymond C. Stevens.

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).

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DOI

https://doi.org/10.1038/nrd3859

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