8fn0 | pdb_00008fn0

CryoEM structure of Go-coupled NTSR1 with a biased allosteric modulator

spinqualitylabelsall models 8fn0, resolution 2.89Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8fn0 is a 6 chain structure with sequence from Escherichia coli, Homo sapiens, Lama glama and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: SRW Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 Mar 14. doi: 10.1021/acs.biochem.3c00029. PMID:36917754 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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