Stabilization of pre-existing neurotensin receptor conformational states by β-arrestin-1 and the biased allosteric modulator ML314

F Bumbak; JB Bower; SC Zemmer; A Inoue; M Pons; JC Paniagua; F Yan; J Ford; H Wu; SA Robson; RAD Bathgate; DJ Scott; PR Gooley; JJ Ziarek

Journal article

Stabilization of pre-existing neurotensin receptor conformational states by β-arrestin-1 and the biased allosteric modulator ML314

F Bumbak, JB Bower, SC Zemmer, A Inoue, M Pons, JC Paniagua, F Yan, J Ford, H Wu, SA Robson, RAD Bathgate, DJ Scott, PR Gooley, JJ Ziarek

Nature Communications | NATURE PORTFOLIO | Published : 2023

DOI: 10.1038/s41467-023-38894-8

Abstract

The neurotensin receptor 1 (NTS1) is a G protein-coupled receptor (GPCR) with promise as a drug target for the treatment of pain, schizophrenia, obesity, addiction, and various cancers. A detailed picture of the NTS1 structural landscape has been established by X-ray crystallography and cryo-EM and yet, the molecular determinants for why a receptor couples to G protein versus arrestin transducers remain poorly defined. We used 13CεH3-methionine NMR spectroscopy to show that binding of phosphatidylinositol-4,5-bisphosphate (PIP2) to the receptor’s intracellular surface allosterically tunes the timescale of motions at the orthosteric pocket and conserved activation motifs – without dramaticall..

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University of Melbourne Researchers

Ross Bathgate Author

Daniel Scott Author

Paul Gooley Author

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Grants

Awarded by Ministerio de Ciencia e Innovación

Funding Acknowledgements

We are grateful to Prof. Aashish Manglik (UCSF) for providing the beta Arr1 construct used in this study. We would like to thank Prof. Andrew L. Lee (UNC) for fruitful discussions. The 14.1 T spectrometer at Indiana University used in this study was generously supported by the Indiana University Fund. Studies at the Florey Institute were supported by the Victorian Government's Operational Infrastructure Support Program. The project was funded by: KAKENHI 21H04791 (A.I.), 21H051130 (A.I.), and JPJSBP120213501 (A.I.) from Japan Society for the Promotion of Science (JSPS); LEAP JP20gm0010004 (A.I.), and BINDS JP20am0101095 (A.I.) from the Japan Agency for Medical Research and Development (AMED); FOREST Program 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 Maeztu grant CEX2021-001202-M (J.C.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 Health (NIH) grants R00GM115814 (J.J.Z.) and R35GM143054 (J.J.Z.).