Structural insights into G-protein-coupled receptor allostery

Abstract

G-protein-coupled receptors (GPCRs) are key cell-surface proteins that transduce external environmental cues into biochemical signals across the membrane. GPCRs are intrinsically allosteric proteins; they interact via spatially distinct yet conformationally linked domains with both endogenous and exogenous proteins, nutrients, metabolites, hormones, small molecules and biological agents. Here we explore recent high-resolution structural studies, which are beginning to unravel the atomic details of allosteric transitions that govern GPCR biology, as well as highlighting how the wide diversity of druggable allosteric sites across these receptors present opportunities for developing new classes of therapeutics.

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Fig. 1: A continuum of GPCR conformational states.
Fig. 2: Diversity in the binding sites of synthetic allosteric modulators across GPCR classes.
Fig. 3: Cholesterol-binding sites across GPCRs.
Fig. 4: Conformational mechanisms of biased agonism.

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Acknowledgements

We are grateful to J. Tesmer for assistance with preparation of Supplementary Table 1. This work was funded by the National Health and Medical Research Council of Australia (NHMRC) (Program Grant number APP1055134). D.M.T. and A.G. are Australian Research Council Discovery Early Career Research Award Fellows, P.M.S. is a NHMRC Principal Research Fellow and A.C. is a NHMRC Senior Principal Research Fellow.

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Nature thanks A. Jazayeri, R. Lefkowitz and A. Manglik for their contribution to the peer review of this work.

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Thal, D.M., Glukhova, A., Sexton, P.M. et al. Structural insights into G-protein-coupled receptor allostery. Nature 559, 45–53 (2018). https://doi.org/10.1038/s41586-018-0259-z

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