Determinants of Ligand Subtype-Selectivity at α 1A -Adrenoceptor Revealed Using Saturation Transfer Difference (STD) NMR

KJ Yong; TM Vaid; PJ Shilling; FJ Wu; LM Williams; M Deluigi; A Plückthun; RAD Bathgate; PR Gooley; DJ Scott

Journal article

Determinants of Ligand Subtype-Selectivity at α 1A -Adrenoceptor Revealed Using Saturation Transfer Difference (STD) NMR

KJ Yong, TM Vaid, PJ Shilling, FJ Wu, LM Williams, M Deluigi, A Plückthun, RAD Bathgate, PR Gooley, DJ Scott

ACS Chemical Biology | AMER CHEMICAL SOC | Published : 2018

DOI: 10.1021/acschembio.8b00191

Abstract

α 1A - and α 1B -adrenoceptors (α 1A -AR and α 1B -AR) are closely related G protein-coupled receptors (GPCRs) that modulate the cardiovascular and nervous systems in response to binding epinephrine and norepinephrine. The GPCR gene superfamily is made up of numerous subfamilies that, like α 1A -AR and α 1B -AR, are activated by the same endogenous agonists but may modulate different physiological processes. A major challenge in GPCR research and drug discovery is determining how compounds interact with receptors at the molecular level, especially to assist in the optimization of drug leads. Nuclear magnetic resonance spectroscopy (NMR) can provide great insight into ligand-binding epitopes,..

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University of Melbourne Researchers

Ross Bathgate Author

Paul Gooley Author

Daniel Scott Author

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Grants

Awarded by Australian Research Council

Funding Acknowledgements

We thank V. Jameson and J. Kie (MBC Flow Cytometry Facility) for assistance with FAGS, as well as S. Layfield, T. Ferraro, and M. Petrovska for cell-based assays and R Cridge and L. C. Cardinal for assistance with characterizing the purified alpha<INF>1</INF>-ARs (all from The Florey Institute of Neuroscience and Mental Health). This work was supported by NHMRC project grants 1081801 (D.J.S) and 1081844 (R.A.D.B, P.R.G, D.J.S); ARC equipment grant LE120100022. D.J.S. is an NHMRC Boosting Dementia Research Leadership Fellow. R.A.D.B. is an NHMRC Senior Research Fellow. Studies at The Florey Institute of Neuroscience and Mental Health were supported by the Victorian Government's Operational Infrastructure Support Program. Studies at the University of Zurich were supported by Schweizerischer Nationalfonds grant 31003A_153143 (to A.P.).