8V88

Alpha7-nicotinic acetylcholine receptor bound to epibatidine and GAT107

8V88 の概要

• エントリーDOI: 10.2210/pdb8v88/pdb
• 関連するPDBエントリー: 8UT1 8UTB 8UZJ 8V80 8V82 8V86 8V89 8V8A 8V8C 8V8D
• EMDBエントリー: 43030
• 分子名称: Neuronal acetylcholine receptor subunit alpha-7,Soluble cytochrome b562, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• 機能のキーワード: ion channel, membrane protein, nicotinic receptor
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 355859.90

構造登録者

Burke, S.M.,Noviello, C.M.,Hibbs, R.E. (登録日: 2023-12-05, 公開日: 2024-02-21, 最終更新日: 2024-10-23)

主引用文献

Burke, S.M.,Avstrikova, M.,Noviello, C.M.,Mukhtasimova, N.,Changeux, J.P.,Thakur, G.A.,Sine, S.M.,Cecchini, M.,Hibbs, R.E.
Structural mechanisms of alpha 7 nicotinic receptor allosteric modulation and activation.
Cell, 187:1160-1176.e21, 2024

PubMed Abstract: The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in cholinergic signaling throughout the nervous system. Its unique physiological characteristics and implications in neurological disorders and inflammation make it a promising but challenging therapeutic target. Positive allosteric modulators overcome limitations of traditional α7 agonists, but their potentiation mechanisms remain unclear. Here, we present high-resolution structures of α7-modulator complexes, revealing partially overlapping binding sites but varying conformational states. Structure-guided functional and computational tests suggest that differences in modulator activity arise from the stable rotation of a channel gating residue out of the pore. We extend the study using a time-resolved cryoelectron microscopy (cryo-EM) approach to reveal asymmetric state transitions for this homomeric channel and also find that a modulator with allosteric agonist activity exploits a distinct channel-gating mechanism. These results define mechanisms of α7 allosteric modulation and activation with implications across the pentameric receptor superfamily.

PubMed: 38382524
DOI: 10.1016/j.cell.2024.01.032

実験手法

ELECTRON MICROSCOPY (2.3 Å)