生物物理学
门控
生物
心跳
钠通道
突变
电导
细胞内
钠
细胞生物学
突变
生物化学
材料科学
物理
计算机安全
计算机科学
凝聚态物理
基因
冶金
作者
Dequan Jiang,Richard L. Banh,Tamer M. Gamal El-Din,Lige Tonggu,Michael J. Lenaeus,Régis Pomès,Ning Zheng,William A. Catterall
出处
期刊:Cell
[Elsevier]
日期:2021-09-01
卷期号:184 (20): 5151-5162.e11
被引量:57
标识
DOI:10.1016/j.cell.2021.08.021
摘要
The heartbeat is initiated by voltage-gated sodium channel NaV1.5, which opens rapidly and triggers the cardiac action potential; however, the structural basis for pore opening remains unknown. Here, we blocked fast inactivation with a mutation and captured the elusive open-state structure. The fast inactivation gate moves away from its receptor, allowing asymmetric opening of pore-lining S6 segments, which bend and rotate at their intracellular ends to dilate the activation gate to ∼10 Å diameter. Molecular dynamics analyses predict physiological rates of Na+ conductance. The open-state pore blocker propafenone binds in a high-affinity pose, and drug-access pathways are revealed through the open activation gate and fenestrations. Comparison with mutagenesis results provides a structural map of arrhythmia mutations that target the activation and fast inactivation gates. These results give atomic-level insights into molecular events that underlie generation of the action potential, open-state drug block, and fast inactivation of cardiac sodium channels, which initiate the heartbeat.
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