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

The neurotensin receptor 1 (NTS(1)) 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 NTS(1) structural landscape has been established by X-ray crystallography and cryo-EM...

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Detalles Bibliográficos
Autores principales: Bumbak, Fabian, Bower, James B., Zemmer, Skylar C., Inoue, Asuka, Pons, Miquel, Paniagua, Juan Carlos, Yan, Fei, Ford, James, Wu, Hongwei, Robson, Scott A., Bathgate, Ross A. D., Scott, Daniel J., Gooley, Paul R., Ziarek, Joshua J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10247727/
https://www.ncbi.nlm.nih.gov/pubmed/37286565
http://dx.doi.org/10.1038/s41467-023-38894-8
Descripción
Sumario:The neurotensin receptor 1 (NTS(1)) 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 NTS(1) 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 (13)C(ε)H(3)-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 dramatically altering the structural ensemble. β-arrestin-1 further remodels the receptor ensemble by reducing conformational exchange kinetics for a subset of resonances, whereas G protein coupling has little to no effect on exchange rates. A β-arrestin biased allosteric modulator transforms the NTS(1):G protein complex into a concatenation of substates, without triggering transducer dissociation, suggesting that it may function by stabilizing signaling incompetent G protein conformations such as the non-canonical state. Together, our work demonstrates the importance of kinetic information to a complete picture of the GPCR activation landscape.