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- Title
Conformational plasticity of ligand-bound and ternary GPCR complexes studied by 19F NMR of the β1-adrenergic receptor.
- Authors
Frei, J. Niclas; Broadhurst, Richard W.; Bostock, Mark J.; Solt, Andras; Jones, Andrew J. Y.; Gabriel, Florian; Tandale, Aditi; Shrestha, Binesh; Nietlispach, Daniel
- 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. The β1-adrenergic receptor (β1AR) is a G-protein-coupled receptor (GPCRs) that binds catecholamine ligands. Here the authors employ site-specific labelling and 19F NMR measurements to characterise the structural changes and dynamics in the cytoplasmic region of β1AR upon agonist stimulation and coupling to a Gs-protein-mimetic nanobody.
- Subjects
ADRENERGIC receptors; ALLOSTERIC proteins; TERNARY forms; STRUCTURAL dynamics; CELL membranes; BETA adrenoceptors; LABELS
- Publication
Nature Communications, 2020, Vol 11, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-14526-3