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Molecular signatures of G-protein-coupled receptors

Nature volume 494, pages 185–194 (2013)Cite this article

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Abstract

G-protein-coupled receptors (GPCRs) are physiologically important membrane proteins that sense signalling molecules such as hormones and neurotransmitters, and are the targets of several prescribed drugs. Recent exciting developments are providing unprecedented insights into the structure and function of several medically important GPCRs. Here, through a systematic analysis of high-resolution GPCR structures, we uncover a conserved network of non-covalent contacts that defines the GPCR fold. Furthermore, our comparative analysis reveals characteristic features of ligand binding and conformational changes during receptor activation. A holistic understanding that integrates molecular and systems biology of GPCRs holds promise for new therapeutics and personalized medicine.

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Figure 1: Time-line of GPCR structures.
Figure 2: Diversity in the secondary structure elements of GPCRs in the extracellular and intracellular regions.
Figure 3: Consensus scaffold of non-covalent contacts in GPCRs.
Figure 4: Ligand-binding pocket in class A GPCRs.
Figure 5: Characterization of G-protein-binding region within TM helices of GPCRs.
Figure 6: Structural and functional hub role of TM3.

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Acknowledgements

We thank A. Deonarine, C. Chothia, D. Ghosal, J. Marsh, J. Garcia-Nafria, K. R. Vinothkumar, R. Henderson, R. Hegde, S. Balaji, S. Chavali and T. Flock for their comments on this work. This work was supported by the UK Medical Research Council (U105185859), HFSP (RGY0073/2010; M.M.B.), the EMBO Young Investigator Program (M.M.B.), and ERASysBio+ (GRAPPLE; M.M.B.). A.J.V. acknowledges LMB Cambridge Scholarship and St. John’s College Benefactor Scholarship for financial support. G.L. was funded by Heptares Therapeutics, the UK Medical Research Council and by the CNRS and Agence Nationale de la Recherche (grant ANR-09-BLAN-0272). X.D. and G.F.S. acknowledge the Swiss National Science Foundation (grant 31003A_132815) and the ETH Zürich within the framework of the National Center for Competence in Research in Structural Biology Program for financial support. C.G.T. acknowledges the Medical Research Council Technology Development Gap Fund, Pfizer, and core funding from the UK Medical Research Council (U105197215). We apologize to our colleagues whose work was not cited owing to space limitations.

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Authors and Affiliations

  1. MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK,

    A. J. Venkatakrishnan, Guillaume Lebon, Christopher G. Tate & M. Madan Babu

  2. Paul Scherrer Institute, 5232 Villigen PSI, Switzerland,

    Xavier Deupi & Gebhard F. Schertler

  3. CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier F-34094, France,

    Guillaume Lebon

  4. INSERM, U661, Montpellier F-34094, France,

    Guillaume Lebon

  5. Universités de Montpellier 1 & 2, UMR-5203, Montpellier F-34094, France,

    Guillaume Lebon

  6. Department of Biology, ETH Zürich, Wolfgang-Pauli-Str. 27, 8093 Zürich, Switzerland,

    Gebhard F. Schertler

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  1. A. J. Venkatakrishnan
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Contributions

A.J.V. and M.M.B. designed the study, analysed the results and wrote the manuscript. A.J.V. performed all calculations. X.D., G.L., C.G.T. and G.F.S. provided data, and contributed to the analysis and writing of the manuscript.

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This file contains Supplementary Table 2 which shows consensus inter-TM contact network of the GPCR fold and Supplementary Table 3 which shows topologically equivalent residues across the different GPCRs. (XLSX 106 kb)

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Venkatakrishnan, A., Deupi, X., Lebon, G. et al. Molecular signatures of G-protein-coupled receptors. Nature 494, 185–194 (2013). https://doi.org/10.1038/nature11896

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  • DOI: https://doi.org/10.1038/nature11896

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