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A kinetic view of GPCR allostery and biased agonism

Nature Chemical Biology volume 13, pages 929–937 (2017)Cite this article

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Abstract

G-protein-coupled receptors (GPCRs) are one of the most tractable classes of drug targets. These dynamic proteins can adopt multiple active states that are linked to distinct functional outcomes. Such states can be differentially stabilized by ligands interacting with the endogenous agonist-binding orthosteric site and/or by ligands acting via spatially distinct allosteric sites, leading to the phenomena of 'biased agonism' or 'biased modulation'. These paradigms are having a major impact on modern drug discovery, but it is becoming increasingly apparent that 'kinetic context', at the level of both ligand–receptor and receptor—signal pathway kinetics, can have a profound impact on the observation and quantification of these phenomena. The concept of kinetic context thus represents an important new consideration that should be routinely incorporated into contemporary chemical biology and drug discovery studies of GPCR bias and allostery.

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Figure 1: Biased agonism and biased modulation.
Figure 2: Common analytical models of ligand action at GPCRs.
Figure 3: Effects of allosteric-modulator-mediated changes in binding kinetics on the equilibrium behavior of orthosteric ligands.
Figure 4: The extracellular vestibule of rhodopsin-like GPCRs can control the access and egress of orthosteric ligands, and can contribute to the formation of a binding site for allosteric modulators.
Figure 5: Failure to attain equilibrium between orthosteric and allosteric ligands can lead to apparently complex behaviors of allosteric modulators.
Figure 6: Kinetic context can have a profound impact on the quantification of biased agonism.

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Acknowledgements

We thank D. Thal (Monash University) for assistance in generating Figure 4a and R. Dror (Stanford University) for providing us with PDB files for generating Figure 5a. A.C. and R.G.P. are Senior Principal, and P.M.S. Principal, Research Fellows of the National Health and Medical Research Council (NHMRC) of Australia. J.R.L. is an R D Wright Biomedical Career Development Fellow (NHMRC). L.T.M. is a DECRA Postdoctoral Research Fellow of the Australian Research Council.

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  1. J Robert Lane and Lauren T May: These authors contributed equally to this work.

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  1. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia

    J Robert Lane, Lauren T May, Patrick M Sexton & Arthur Christopoulos

  2. Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia

    Robert G Parton

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Lane, J., May, L., Parton, R. et al. A kinetic view of GPCR allostery and biased agonism. Nat Chem Biol 13, 929–937 (2017). https://doi.org/10.1038/nchembio.2431

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