6OBA

The beta2 adrenergic receptor bound to a negative allosteric modulator

6OBA の概要

• エントリーDOI: 10.2210/pdb6oba/pdb
• 分子名称: Beta-2 adrenergic receptor,Lysozyme,Beta-2 adrenergic receptor, CHOLESTEROL, (2S)-1-[(1-methylethyl)amino]-3-(2-prop-2-en-1-ylphenoxy)propan-2-ol, ... (4 entities in total)
• 機能のキーワード: g protein coupled receptors, signal transduction, allosteric modulators, membrane protein, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 57939.26

構造登録者

Liu, X.,Stobel, A.,Kaindl, J.,Dengler, D.,ClarK, M.,Mahoney, J.,Korczynska, M.,Matt, R.A.,Hubner, H.,Xu, X.,Stanek, M.,Hirata, K.,Shoichet, B.,Sunahara, R.,Gmeiner, R.,Kobilka, B.K. (登録日: 2019-03-20, 公開日: 2020-03-25, 最終更新日: 2024-11-20)

主引用文献

Liu, X.,Kaindl, J.,Korczynska, M.,Stossel, A.,Dengler, D.,Stanek, M.,Hubner, H.,Clark, M.J.,Mahoney, J.,Matt, R.A.,Xu, X.,Hirata, K.,Shoichet, B.K.,Sunahara, R.K.,Kobilka, B.K.,Gmeiner, P.
An allosteric modulator binds to a conformational hub in the beta2adrenergic receptor.
Nat.Chem.Biol., 16:749-755, 2020

PubMed Abstract: Most drugs acting on G-protein-coupled receptors target the orthosteric binding pocket where the native hormone or neurotransmitter binds. There is much interest in finding allosteric ligands for these targets because they modulate physiologic signaling and promise to be more selective than orthosteric ligands. Here we describe a newly developed allosteric modulator of the β-adrenergic receptor (βAR), AS408, that binds to the membrane-facing surface of transmembrane segments 3 and 5, as revealed by X-ray crystallography. AS408 disrupts a water-mediated polar network involving E122 and the backbone carbonyls of V206 and S207. The AS408 binding site is adjacent to a previously identified molecular switch for βAR activation formed by I, P and F. The structure reveals how AS408 stabilizes the inactive conformation of this switch, thereby acting as a negative allosteric modulator for agonists and positive allosteric modulator for inverse agonists.

PubMed: 32483378
DOI: 10.1038/s41589-020-0549-2

実験手法

X-RAY DIFFRACTION (3.1 Å)