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

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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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.

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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.

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Correspondence to Raymond C. Stevens.

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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.

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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).

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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

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