Conformational plasticity of ligand-bound and ternary GPCR complexes studied by 19F NMR of the β1-adrenergic receptor.
Frei, J Niclas
Jones, Andrew JY
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Frei, J. N., Broadhurst, B., Bostock, M. J., Solt, A., Jones, A. J., Gabriel, F., Tandale, A., et al. (2020). Conformational plasticity of ligand-bound and ternary GPCR complexes studied by 19F NMR of the β1-adrenergic receptor.. Nature communications, 11 (1), 669. https://doi.org/10.1038/s41467-020-14526-3
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.
BBSRC (BB/K01983 X/1)
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External DOI: https://doi.org/10.1038/s41467-020-14526-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/300844
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