Binding kinetics drive G protein subtype selectivity at the β1-adrenergic receptor

Andrew J. Y. Jones, Thomas H. Harman, Matthew Harris, Oliver E. Lewis, Graham Ladds and Daniel Nietlispach ()
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Andrew J. Y. Jones: University of Cambridge
Thomas H. Harman: University of Cambridge
Matthew Harris: University of Cambridge
Oliver E. Lewis: University of Cambridge
Graham Ladds: University of Cambridge
Daniel Nietlispach: University of Cambridge

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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 13C methyl methionine and 19F NMR, we investigate the agonist-bound active state of β1AR 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 β1AR in ternary complexes. Assessing the kinetics of binding for the agonist-bound receptor with different G proteins, we find the increased affinity of β1AR for Gs 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.

Date: 2024
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DOI: 10.1038/s41467-024-45680-7

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