Unravelling the mechanism of neurotensin recognition by neurotensin receptor 1

K Asadollahi; S Rajput; LA de Zhang; CS Ang; S Nie; NA Williamson; MDW Griffin; RAD Bathgate; DJ Scott; TR Weikl; GNL Jameson; PR Gooley

Journal article

Unravelling the mechanism of neurotensin recognition by neurotensin receptor 1

K Asadollahi, S Rajput, LA de Zhang, CS Ang, S Nie, NA Williamson, MDW Griffin, RAD Bathgate, DJ Scott, TR Weikl, GNL Jameson, PR Gooley

Nature Communications | NATURE PORTFOLIO | Published : 2023

DOI: 10.1038/s41467-023-44010-7

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Abstract

The conformational ensembles of G protein-coupled receptors (GPCRs) include inactive and active states. Spectroscopy techniques, including NMR, show that agonists, antagonists and other ligands shift the ensemble toward specific states depending on the pharmacological efficacy of the ligand. How receptors recognize ligands and the kinetic mechanism underlying this population shift is poorly understood. Here, we investigate the kinetic mechanism of neurotensin recognition by neurotensin receptor 1 (NTS1) using 19F-NMR, hydrogen-deuterium exchange mass spectrometry and stopped-flow fluorescence spectroscopy. Our results indicate slow-exchanging conformational heterogeneity on the extracellular..

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University of Melbourne Researchers

Sunnia Rajput Author

Ching-Seng Ang Author

Nicholas Williamson Author

Michael Griffin Author

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Grants

Awarded by Northwestern University

Funding Acknowledgements

This work was supported by National Health and Medical Research Council (NHMRC) project Grants 1081844 and 1141034 (to P.R.G., D.J.S. and R.A.D.B.) and a NHMRC Boosting Dementia Research Leadership Fellowship (to D.J.S.). K.A. is recipient of a Melbourne Research Scholarship. We acknowledge the use of the NMR and Mass Spectrometry facilities at the University of Melbourne. The chimeric G alpha iq construct used in this study was a generous gift from A/Prof Joshua Ziarek, Northwestern University.