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

Kelvin J Yong; Tasneem M Vaid; Patrick J Shilling; Feng-Jie Wu; Lisa M Williams; Mattia Deluig; Andreas Plueckthun; Ross AD Bathgate; Paul R Gooley; Daniel J Scott

Journal article

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

Kelvin J Yong, Tasneem M Vaid, Patrick J Shilling, Feng-Jie Wu, Lisa M Williams, Mattia Deluig, Andreas Plueckthun, Ross AD Bathgate, Paul R Gooley, Daniel J Scott

ACS CHEMICAL BIOLOGY | AMER CHEMICAL SOC | Published : 2018

DOI: 10.1021/acschembio.8b00191

Abstract

α1A- and α1B-adrenoceptors (α1A-AR and α1B-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 α1A-AR and α1B-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, modes, and ..

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University of Melbourne Researchers

Paul Gooley Author Biochemistry and Pharmacology

Daniel Scott Author Florey Department of Neuroscience and Mental Health

Ross Bathgate Author Florey Department of Neuroscience and Mental Health

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Grants

Awarded by NHMRC

Awarded by ARC

Awarded by Schweizerischer Nationalfonds

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.).