Insight into Partial Agonism by Observing Multiple Equilibria for Ligand-bound and G-mimetic Nanobody-bound β-adrenergic Receptor

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Nov 28

PMID 29176642

Citations 47

Authors

Andras S Solt

Mark J Bostock

Binesh Shrestha

Prashant Kumar

Tony Warne

Christopher G Tate

Daniel Nietlispach

Affiliations

Soon will be listed here.

Abstract

A complex conformational energy landscape determines G-protein-coupled receptor (GPCR) signalling via intracellular binding partners (IBPs), e.g., G and β-arrestin. Using C methyl methionine NMR for the β-adrenergic receptor, we identify ligand efficacy-dependent equilibria between an inactive and pre-active state and, in complex with G-mimetic nanobody, between more and less active ternary complexes. Formation of a basal activity complex through ligand-free nanobody-receptor interaction reveals structural differences on the cytoplasmic receptor side compared to the full agonist-bound nanobody-coupled form, suggesting that ligand-induced variations in G-protein interaction underpin partial agonism. Significant differences in receptor dynamics are observed ranging from rigid nanobody-coupled states to extensive μs-to-ms timescale dynamics when bound to a full agonist. We suggest that the mobility of the full agonist-bound form primes the GPCR to couple to IBPs. On formation of the ternary complex, ligand efficacy determines the quality of the interaction between the rigidified receptor and an IBP and consequently the signalling level.

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