Probing the correlation between ligand efficacy and conformational diversity at the ?(1A)-adrenoreceptor reveals allosteric coupling of its microswitches
AuthorWu, F-J; Williams, LM; Abdul-Ridha, A; Gunatilaka, A; Vaid, TM; Kocan, M; Whitehead, AR; Griffin, MDW; Bathgate, RAD; Scott, DJ; ...
Source TitleJournal of Biological Chemistry
PublisherAmerican Society for Biochemistry and Molecular Biology
University of Melbourne Author/sGooley, Paul; Griffin, Michael; Bathgate, Ross; Scott, Daniel; Whitehead, Alice; Kocan, Martina; Abdul-Ridha, Alaa; Williams, Lisa; Gunatilaka, Avanka; Wu, Fengjie; ...
AffiliationBiochemistry and Molecular Biology
Florey Department of Neuroscience and Mental Health
Pharmacology and Therapeutics
Document TypeJournal Article
CitationsWu, F. -J., Williams, L. M., Abdul-Ridha, A., Gunatilaka, A., Vaid, T. M., Kocan, M., Whitehead, A. R., Griffin, M. D. W., Bathgate, R. A. D., Scott, D. J. & Gooley, P. R. (2020). Probing the correlation between ligand efficacy and conformational diversity at the ?(1A)-adrenoreceptor reveals allosteric coupling of its microswitches. Journal of Biological Chemistry, 295 (21), pp.7404-7417. https://doi.org/10.1074/jbc.RA120.012842.
Access StatusOpen Access
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247315
G protein–coupled receptors (GPCRs) use a series of conserved microswitches to transmit signals across the cell membrane via an allosteric network encompassing the ligand-binding site and the G protein-binding site. Crystal structures of GPCRs provide snapshots of their inactive and active states, but poorly describe the conformational dynamics of the allosteric network that underlies GPCR activation. Here, we analyzed the correlation between ligand binding and receptor conformation of the α1A-adrenoreceptor, a GPCR that stimulates smooth muscle contraction in response to binding noradrenaline. NMR of [13CϵH3]methionine-labeled α1A-adrenoreceptor variants, each exhibiting differing signaling capacities, revealed how different classes of ligands modulate the conformational equilibria of this receptor. [13CϵH3]Methionine residues near the microswitches exhibited distinct states that correlated with ligand efficacies, supporting a conformational selection mechanism. We propose that allosteric coupling among the microswitches controls the conformation of the α1A-adrenoreceptor and underlies the mechanism of ligand modulation of GPCR signaling in cells.
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