Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator

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 G alpha 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.

Automated summary

The NTSR1 receptor is a GPCR found in the brain and peripheral tissues that binds with the endogenous peptide ligand NTS. Recent studies have shown that biasing NTSR1 towards beta-arrestin signaling can attenuate the effects of psychostimulants and drugs of abuse. This study provides cryoEM structures of NTSR1 complexes with Gq and GoA, and discusses the allosteric modulation of NTSR1 by the small-molecule SBI-553.