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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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.
The authors declare no competing financial interests.
This file contains suggestions for further reading, Supplementary Table 1 and Supplementary References. (PDF 260 kb)
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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