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Publication Abstract from PubMed

The NTSR1 neurotensin receptor (NTSR1) is a G protein-coupled receptor (GPCR) found in the brain and peripheral tissues with neurotensin (NTS) being its endogenous peptide ligand. In the brain, NTS modulates dopamine neuronal activity, induces opioid-independent analgesia, and regulates food intake. Recent studies indicate that biasing NTSR1 toward beta-arrestin signaling can attenuate the actions of psychostimulants and other drugs of abuse. Here, we provide the cryoEM structures of NTSR1 ternary complexes with heterotrimeric Gq and GoA with and without the brain-penetrant small-molecule SBI-553. In functional studies, we discovered that SBI-553 displays complex allosteric actions exemplified by negative allosteric modulation for G proteins that are Galpha subunit selective and positive allosteric modulation and agonism for beta-arrestin translocation at NTSR1. Detailed structural analysis of the allosteric binding site illuminated the structural determinants for biased allosteric modulation of SBI-553 on NTSR1.

Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator.,Krumm BE, DiBerto JF, Olsen RHJ, Kang HJ, Slocum ST, Zhang S, Strachan RT, Huang XP, Slosky LM, Pinkerton AB, Barak LS, Caron MG, Kenakin T, Fay JF, Roth BL Biochemistry. 2023 Apr 4;62(7):1233-1248. doi: 10.1021/acs.biochem.3c00029. Epub , 2023 Mar 14. PMID:36917754^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.