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

• Published in: Nature communications 2024-02, Vol.15 (1), p.1334-17, Article 1334
• Main Authors: Jones, Andrew J. Y., Harman, Thomas H., Harris, Matthew, Lewis, Oliver E., Ladds, Graham, Nietlispach, Daniel
• Format: Article
• Language: English
• Subjects: 101/6; 631/45/612/194; 631/535/878/1263; 631/57/2272/1590; Adrenergic receptors; Agonists; Binding; Complex formation; G protein-coupled receptors; Humanities and Social Sciences; Intermediates; Kinetics; Methionine; multidisciplinary; NMR; Nuclear magnetic resonance; Proteins; Receptors (physiology); Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45680-7

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 13 C methyl methionine and 19 F NMR, we investigate the agonist-bound active state of β 1 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 1 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 1 AR for G s 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. The authors show G protein subtype selectivity at the β 1 -adrenergic receptor is driven by the binding kinetics of ternary complex formation. Bound to G protein, the receptor adopts conformations that differ from its agonist-bound solution states.