8FMZ

Neurotensin receptor allosterism revealed in complex with a biased allosteric modulator

8FMZ の概要

• エントリーDOI: 10.2210/pdb8fmz/pdb
• EMDBエントリー: 29301
• 分子名称: MiniGq, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• 機能のキーワード: gpcr, neurotensin receptor, allosterism, sbi-553, membrane protein
• 由来する生物種: Escherichia coli; 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 150284.66

構造登録者

Krumm, B.E.,Diberto, J.F.,Olsen, R.H.J.,Kang, H.,Slocum, S.T.,Zhang, S.,Strachan, R.T.,Fay, J.F.,Roth, B.L. (登録日: 2022-12-26, 公開日: 2023-03-29, 最終更新日: 2024-10-30)

主引用文献

Krumm, B.E.,DiBerto, J.F.,Olsen, R.H.J.,Kang, H.J.,Slocum, S.T.,Zhang, S.,Strachan, R.T.,Huang, X.P.,Slosky, L.M.,Pinkerton, A.B.,Barak, L.S.,Caron, M.G.,Kenakin, T.,Fay, J.F.,Roth, B.L.
Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator.
Biochemistry, 62:1233-1248, 2023

PubMed Abstract: 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 β-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 Gα subunit selective and positive allosteric modulation and agonism for β-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.

PubMed: 36917754
DOI: 10.1021/acs.biochem.3c00029

実験手法

ELECTRON MICROSCOPY (2.59 Å)