Unravelling the mechanism of neurotensin recognition by neurotensin receptor 1

Unravelling the mechanism of neurotensin recognition by neurotensin receptor 1

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 rec...

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Bibliographic Details
Published in:Nature communications Vol. 14; no. 1; p. 8155
Main Authors: Asadollahi, Kazem, Rajput, Sunnia, de Zhang, Lazarus Andrew, Ang, Ching-Seng, Nie, Shuai, Williamson, Nicholas A., Griffin, Michael D. W., Bathgate, Ross A. D., Scott, Daniel J., Weikl, Thomas R., Jameson, Guy N. L., Gooley, Paul R.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 09-12-2023
Nature Publishing Group
Nature Portfolio
Subjects:
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Antagonists
Binding
Deuterium
Exchanging
Fluorescence
Fluorescence spectroscopy
G protein-coupled receptors
Heterogeneity
Humanities and Social Sciences
Hydrogen-deuterium exchange
Ligands
Mass spectrometry
Mass spectroscopy
multidisciplinary
Neurotensin
NMR
Nuclear magnetic resonance
Numerical analysis
Receptors
Recognition
Science
Science (multidisciplinary)
Spectroscopy
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Description
Summary: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 (NTS 1 ) using 19 F-NMR, hydrogen-deuterium exchange mass spectrometry and stopped-flow fluorescence spectroscopy. Our results indicate slow-exchanging conformational heterogeneity on the extracellular surface of ligand-bound NTS 1 . Numerical analysis of the kinetic data of neurotensin binding to NTS 1 shows that ligand recognition follows an induced-fit mechanism, in which conformational changes occur after neurotensin binding. This approach is applicable to other GPCRs to provide insight into the kinetic regulation of ligand recognition by GPCRs. GPCRs include inactive and active states. 19 F-NMR and stopped-flow fluorescence kinetic assays reveal that neurotensin activates the prototypical peptide-binding GPCR, neurotensin receptor 1, through an induced-fit mechanism, where ligand binding precedes receptor conformational changes.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-44010-7