Binding Kinetics Drive G Protein Subtype Selectivity at the β-adrenergic Receptor

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Feb 13

PMID 38351103

Authors

Andrew J Y Jones

Thomas H Harman

Matthew Harris

Oliver E Lewis

Graham Ladds

Daniel Nietlispach

Affiliations

Soon will be listed here.

Abstract

G protein-coupled receptors (GPCRs) bind to different G protein α-subtypes with varying degrees of selectivity. The mechanism by which GPCRs achieve this selectivity is still unclear. Using C methyl methionine and F NMR, we investigate the agonist-bound active state of βAR and its ternary complexes with different G proteins in solution. We find the receptor in the ternary complexes adopts very similar conformations. In contrast, the full agonist-bound receptor active state assumes a conformation differing from previously characterised activation intermediates or from βAR in ternary complexes. Assessing the kinetics of binding for the agonist-bound receptor with different G proteins, we find the increased affinity of βAR for G results from its much faster association with the receptor. Consequently, we suggest a kinetic-driven selectivity gate between canonical and secondary coupling which arises from differential favourability of G protein binding to the agonist-bound receptor active state.

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