9DMK

Human muscle nAChR with one fab1b-bound

9DMK の概要

• エントリーDOI: 10.2210/pdb9dmk/pdb
• EMDBエントリー: 47008
• 分子名称: Acetylcholine receptor subunit alpha, (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (12 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: 7
• 化学式量合計: 336138.26

構造登録者

Li, H.,Hibbs, R.E. (登録日: 2024-09-13, 公開日: 2025-04-09, 最終更新日: 2025-10-22)

主引用文献

Li, H.,Pham, M.C.,Teng, J.,O'Connor, K.C.,Noviello, C.M.,Hibbs, R.E.
Autoimmune mechanisms elucidated through muscle acetylcholine receptor structures.
Cell, 188:2390-2406.e20, 2025

PubMed Abstract: Skeletal muscle contraction is triggered by acetylcholine (ACh) binding to its ionotropic receptors (AChRs) at neuromuscular junctions. In myasthenia gravis (MG), autoantibodies target AChRs, disrupting neurotransmission and causing muscle weakness. While treatments exist, variable patient responses suggest pathogenic heterogeneity. Progress in understanding the molecular basis of MG has been limited by the absence of structures of intact human muscle AChRs. Here, we present high-resolution cryoelectron microscopy (cryo-EM) structures of the human adult AChR in different functional states. Using six MG patient-derived monoclonal antibodies, we mapped distinct epitopes involved in diverse pathogenic mechanisms, including receptor blockade, internalization, and complement activation. Electrophysiological and binding assays revealed how these autoantibodies directly inhibit AChR channel activation. These findings provide critical insights into MG immunopathogenesis, uncovering unrecognized antibody epitope diversity and modes of receptor inhibition, and provide a framework for developing personalized therapies targeting antibody-mediated autoimmune disorders.

PubMed: 40203823
DOI: 10.1016/j.cell.2025.03.004

実験手法

ELECTRON MICROSCOPY (2.46 Å)