Binding kinetics drive G protein subtype selectivity at the β 1 -adrenergic receptor

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 β AR and its ternary complexes...

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Bibliographic Details
Published in:Nature communications 2024-02, Vol.15 (1), p.1334
Main Authors: Jones, Andrew J Y, Harman, Thomas H, Harris, Matthew, Lewis, Oliver E, Ladds, Graham, Nietlispach, Daniel
Format: Article
Language:English
Subjects:
GTP-Binding Proteins - metabolism
Protein Binding
Receptors, G-Protein-Coupled - metabolism
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Summary: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 β AR 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 β AR in ternary complexes. Assessing the kinetics of binding for the agonist-bound receptor with different G proteins, we find the increased affinity of β AR 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.
ISSN:2041-1723