Journal article

Probing the correlation between ligand efficacy and conformational diversity at the ?(1A)-adrenoreceptor reveals allosteric coupling of its microswitches

Feng-Jie Wu, Lisa M Williams, Alaa Abdul-Ridha, Avanka Gunatilaka, Tasneem M Vaid, Martina Kocan, Alice R Whitehead, Michael DW Griffin, Ross AD Bathgate, Daniel J Scott, Paul R Gooley

Journal of Biological Chemistry | American Society for Biochemistry and Molecular Biology | Published : 2020


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..

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Awarded by National Health and Medical Research Council (NHMRC)

Funding Acknowledgements

This work was supported by National Health and Medical Research Council (NHMRC) project Grants 1081801 (to D. J. S.), 1081844 (to P. R. G., D. J. S., and R. A. D. B.), and 1141034 (to D. J. S., P. R. G., and R. A. D. B.), and a NHMRC Boosting Dementia Research Leadership Fellowship (to D. J. S.). The authors declare that they have no conflicts of interest with the contents of this article.