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

Fabian Bumbak (), James B. Bower, Skylar C. Zemmer, Asuka Inoue, Miquel Pons, Juan Carlos Paniagua, Fei Yan, James Ford, Hongwei Wu, Scott A. Robson, Ross A. D. Bathgate, Daniel J. Scott, Paul R. Gooley and Joshua J. Ziarek ()
Additional contact information
Fabian Bumbak: Indiana University
James B. Bower: Indiana University
Skylar C. Zemmer: Indiana University
Asuka Inoue: Tohoku University
Miquel Pons: Universitat de Barcelona (UB)
Juan Carlos Paniagua: Universitat de Barcelona (UB)
Fei Yan: University of Melbourne
James Ford: Indiana University
Hongwei Wu: Indiana University
Scott A. Robson: Indiana University
Ross A. D. Bathgate: The University of Melbourne
Daniel J. Scott: The University of Melbourne
Paul R. Gooley: University of Melbourne
Joshua J. Ziarek: Indiana University

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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 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 NTS1: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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-38894-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38894-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-38894-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().