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Title: Ligand-dependent modulation of G protein conformation alters drug efficacy
Austin Authors: Furness, Sebastian GB;Liang, Yi-Lynn;Nowell, Cameron J;Halls, Michelle L;Wookey, Peter J ;Dal Maso, Emma;Inoue, Asuka;Christopoulos, Arthur;Wootten, Denise;Sexton, Patrick M
Affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia
Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Japan
Japan Science and Technology Agency (JST), Precursory Research for Embryonic Sciences and Technology (PRESTO), Kawaguchi, Saitama, Japan
Issue Date: 20-Oct-2016 2016-10-06
Publication information: Cell 2016; 167(3): 739-749
Abstract: G protein-coupled receptor (GPCR) signaling, mediated by hetero-trimeric G proteins, can be differentially controlled by agonists. At a molecular level, this is thought to occur principally via stabilization of distinct receptor conformations by individual ligands. These distinct conformations control subsequent recruitment of transducer and effector proteins. Here, we report that ligand efficacy at the calcitonin GPCR (CTR) is also correlated with ligand-dependent alterations to G protein conformation. We observe ligand-dependent differences in the sensitivity of the G protein ternary complex to disruption by GTP, due to conformational differences in the receptor-bound G protein hetero-trimer. This results in divergent agonist-dependent receptor-residency times for the hetero-trimeric G protein and different accumulation rates for downstream second messengers. This study demonstrates that factors influencing efficacy extend beyond receptor conformation(s) and expands understanding of the molecular basis for how G proteins control/influence efficacy. This has important implications for the mechanisms that underlie ligand-mediated biased agonism.
DOI: 10.1016/j.cell.2016.09.021
ORCID: 0000-0002-3937-1621
Journal: Cell
PubMed URL:
Type: Journal Article
Subjects: BRET
G protein-coupled receptor
Calcitonin receptor
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