Ligands selectively tune the local and global motions of neurotensin receptor 1 (NTS1)

F Bumbak; M Pons; A Inoue; JC Paniagua; F Yan; H Wu; SA Robson; RAD Bathgate; DJ Scott; PR Gooley; JJ Ziarek

Journal article

Ligands selectively tune the local and global motions of neurotensin receptor 1 (NTS1)

F Bumbak, M Pons, A Inoue, JC Paniagua, F Yan, H Wu, SA Robson, RAD Bathgate, DJ Scott, PR Gooley, JJ Ziarek

Cell Reports | CELL PRESS | Published : 2023

DOI: 10.1016/j.celrep.2023.112015

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Abstract

Nuclear magnetic resonance (NMR) studies have revealed that fast methyl sidechain dynamics can report on entropically-driven allostery. Yet, NMR applications have been largely limited to the super-microsecond motional regimes of G protein-coupled receptors (GPCRs). We use 13Cε-methionine chemical shift-based global order parameters to test if ligands affect the fast dynamics of a thermostabilized GPCR, neurotensin receptor 1 (NTS1). We establish that the NTS1 solution ensemble includes substates with lifetimes on several, discrete timescales. The longest-lived states reflect those captured in agonist- and inverse agonist-bound crystal structures, separated by large energy barriers. We observ..

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University of Melbourne Researchers

Ross Bathgate Author

Daniel Scott Author

Paul Gooley Author

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Awarded by National Institutes of Health

Funding Acknowledgements

We would like to thank Dr. Piotr Mroz (Indiana University) for synthesis of NT8-13, Dr. Vanta Jameson and Dr. Josh Kie (The University of Melbourne) for assistance with flow cytometry, and Prof. Andrew L. Lee (The University of North Carolina at Chapel Hill) for fruitful discussions. The 14.1 T spectrometer at Indiana University used in this study was generously supported by the Indiana University Fund. The project was funded by KAKENHI 21H04791 (A.I.) and 21H051130 (A.I.); JPJSBP120213501 (A.I.) from Japan Society for the Promotion of Science (JSPS); LEAP JP20gm0010004 (A.I.); BINDS JP20am0101095 (A.I.) from the Japan Agency for Medical Research and Development (AMED); FOREST JPMJFR215T (A.I.) and JST Moonshot Research and Development Program JPMJMS2023 (A.I.) from Japan Science and Technology Agency (JST); Daiichi Sankyo Foundation of Life Science (A.I.); Takeda Science Foundation (A.I.); Ono Medical Research Foundation (A.I.); Uehara Memorial Foundation (A.I.); Agencia Estatal de Investigacion, Spain grant PID2019-104914RB-I00 (J.C.P. and M.P.); Ministerio de Ciencia e Innovacion, Maria de Maseztu grant CEX2021-001202-M (J.C.P. and M.P.); Australian National Health and Medical Research Council (NHMRC) grants 1081844 and 1141034 (R.A.D.B., D.J.S., and P.R.G.); Indiana Precision Health Initiative (J.J.Z.); and National Institutes of Medicine (NIH) grants R00GM115814 (J.J.Z.) and R35GM143054 (J.J.Z.).