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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Andrew J. Y. Jones & Thomas H. Harman & Matthew Harris & Oliver E. Lewis & Graham Ladds & Daniel Nietlispach, 2024. "Binding kinetics drive G protein subtype selectivity at the β1-adrenergic receptor," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45680-7
    DOI: 10.1038/s41467-024-45680-7
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