9YET

Human muscle nAChR SCCMS eT264P ACh, Reboxetine bound

これはPDB形式変換不可エントリーです。

9YET の概要

• エントリーDOI: 10.2210/pdb9yet/pdb
• EMDBエントリー: 72862
• 分子名称: Acetylcholine receptor subunit alpha, 2-acetamido-2-deoxy-beta-D-glucopyranose, Acetylcholine receptor subunit beta, ... (11 entities in total)
• 機能のキーワード: human muscle, nicotinic acetylcholine receptor, membrane protein
• 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: 268601.13

構造登録者

Li, H.,Hibbs, R.E. (登録日: 2025-09-24, 公開日: 2026-08-05)

主引用文献

Li, H.,Mukhtasimova, N.,Teng, J.,Cavalli, E.S.,Gu, X.,Sello, J.K.,Sine, S.M.,Hibbs, R.E.
Correcting congenital myasthenia-associated acetylcholine receptor defects.
Nature, 2026

PubMed Abstract: Voluntary muscle contraction is triggered by the neurotransmitter acetylcholine binding its receptors on the postsynaptic membrane of the neuromuscular junction, opening ion channels that allow cation influx and initiate depolarization. Mutations in muscle acetylcholine receptors disrupt this process by either impairing (fast-channel) or prolonging (slow-channel) channel openings. These defects cause congenital myasthenic syndromes (CMS), characterized by severe muscle weakness that is often present at birth and, in some cases, progresses to paralysis and death. The structural mechanisms underlying these pathogenic defects and their pharmacological correction remain unknown. Here, using cryogenic electron microscopy, chemical biology and electrophysiology, we determined the structures and functional consequences of representative CMS mutant receptors with and without drugs. In fast-channel disease-associated mutants, we discovered a cryptic allosteric site targeted by positive modulators that restore gating in a mutation-specific manner. In receptor mutants associated with slow-channel disease, quinidine, fluoxetine and reboxetine act as pore blockers; notably, the antidepressant reboxetine selectively blocks desensitized receptors in a mutation-independent fashion, suggesting repurposing potential. Mechanistically, fast-channel mutations uncouple agonist binding from gating, whereas slow-channel mutations stabilize an abnormally widened, desensitized-like pore. These findings reveal unifying principles of CMS pathogenesis and provide a framework for precision therapies.

PubMed: 42386970
DOI: 10.1038/s41586-026-10706-1

実験手法

ELECTRON MICROSCOPY (2.36 Å)