Conformational plasticity of ligand-bound and ternary GPCR complexes studied by 19F NMR of the β1-adrenergic receptor

J. Niclas Frei, Richard W. Broadhurst, Mark J. Bostock, Andras Solt, Andrew J. Y. Jones, Florian Gabriel, Aditi Tandale, Binesh Shrestha and Daniel Nietlispach ()
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J. Niclas Frei: University of Cambridge
Richard W. Broadhurst: University of Cambridge
Mark J. Bostock: University of Cambridge
Andras Solt: University of Cambridge
Andrew J. Y. Jones: University of Cambridge
Florian Gabriel: University of Cambridge
Aditi Tandale: University of Cambridge
Binesh Shrestha: Protein Sciences, CBT, Novartis Institutes for BioMedical Research (NIBR)
Daniel Nietlispach: University of Cambridge

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract G-protein-coupled receptors (GPCRs) are allosteric signaling proteins that transmit an extracellular stimulus across the cell membrane. Using 19F NMR and site-specific labelling, we investigate the response of the cytoplasmic region of transmembrane helices 6 and 7 of the β1-adrenergic receptor to agonist stimulation and coupling to a Gs-protein-mimetic nanobody. Agonist binding shows the receptor in equilibrium between two inactive states and a pre-active form, increasingly populated with higher ligand efficacy. Nanobody coupling leads to a fully active ternary receptor complex present in amounts correlating directly with agonist efficacy, consistent with partial agonism. While for different agonists the helix 6 environment in the active-state ternary complexes resides in a well-defined conformation, showing little conformational mobility, the environment of the highly conserved NPxxY motif on helix 7 remains dynamic adopting diverse, agonist-specific conformations, implying a further role of this region in receptor function. An inactive nanobody-coupled ternary receptor form is also observed.

Date: 2020
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DOI: 10.1038/s41467-020-14526-3

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