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Insight into partial agonism by observing ligand-modulated conformational equilibria of a Gs-mimetic nanobody-bound B1-adrenergic receptor

Solt, Andras and Bostock, Mark J. and Shrestha, Binesh and Kumar, Prashant and Warne, Tony and Tate, Christopher G and Nietlispach, Daniel (2017) Insight into partial agonism by observing ligand-modulated conformational equilibria of a Gs-mimetic nanobody-bound B1-adrenergic receptor. Nature communications, 8. p. 1795. ISSN 2041-1723

Abstract

Signal transduction of extracellular stimuli via G-protein-coupled receptors (GPCRs) involves formation of agonist-bound active receptor complexes with intracellular cytoplasmic binding partners such as G-proteins and β-arrestins. Current mechanistic understanding of activation of these highly dynamic signalling receptors relies primarily on crystallographic information but many questions remain. Using 13C-methyl-methionine NMR we show that following cytoplasmic coupling of Gs-mimetic nanobodies to the β1-adrenergic receptor, the receptor is found in a dynamic ligand-efficacy dependent equilibrium between an active ternary complex when bound to full-agonist and a less-active conformation distinctive of basal activity. Structural differences between the conformations of these ternary complexes concentrate on the cytoplasmic side of the receptor indicating ligand-induced variations in G-protein mimetic interaction as the likely cause, providing a mechanistic framework for partial agonism for the Gs pathway. We compare differences in structure and dynamics for receptors bound to different orthosteric ligands, including observation of states representative of constitutive activity.

Item Type: Article
Date Deposited: 19 Dec 2017 00:45
Last Modified: 19 Dec 2017 00:45
URI: https://oak.novartis.com/id/eprint/33398

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