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Insights into signaling from the β2-adrenergic receptor structure

Nature Chemical Biology volume 4, pages 397–403 (2008)Cite this article

Abstract

With more than 800 members, the G protein–coupled receptor family constitutes the largest group of membrane proteins involved in signal transduction. Until the end of last year, high-resolution three-dimensional structures were available for only one of them—the light receptor rhodopsin. Recently the structure of the β2-adrenergic receptor has been obtained, and it revealed interesting differences with the structure of rhodopsin. Analyses of these differences raise important questions about the binding modes of diffusible ligands in the receptor and allow formulation of testable hypotheses about the structural determinants linking drug binding to specific signaling responses. The three-dimensional structure derived from the β2-adrenergic receptor crystal has been used to virtually dock ligands with distinct activities. The different binding modes of these ligands, which correlated with their reported efficacy profiles, suggest that it could be possible to predict the structural determinants of drug signaling efficacies.

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Figure 1: Illustration of ligand-biased signaling for the β2-AR.
Figure 2: Comparison of carazolol-bound β2-AR and retinal-bound rhodopsin structures.
Figure 3: Comparison of ICL2, ion lock and toggle switch between β2-AR and rhodopsin.
Figure 4: Docking modes of β2-AR ligands with distinct efficacies toward AC and MAPK.

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Acknowledgements

The authors are grateful to C. Le Gouill and A. Marinier for useful discussions, and to the Canadian Institute for Health Research Team in GPCR Allosteric Regulation (CTiGAR), the Direction Générale des Technologies de l'Information et des Communications (DGTIC) of the Université de Montréal and the NMR platform of Institute for Research in Immunology and Cancer (IRIC) for providing access to their servers for simulation and docking.

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  1. Martin Audet and Michel Bouvier are in the Department of Biochemistry, Institute for Research in Immunology and Cancer, and Groupe de Recherche Universitaire sur le Médicament, Université de Montréal, C.P. 6128 Succursale Centre-Ville, Montréal, Québec H3C 3J7, Canada. michel.bouvier@umontreal.ca,

    Martin Audet & Michel Bouvier

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Audet, M., Bouvier, M. Insights into signaling from the β2-adrenergic receptor structure. Nat Chem Biol 4, 397–403 (2008). https://doi.org/10.1038/nchembio.97

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