%0 Journal Article
%T Open-state structure and pore gating mechanism of the cardiac sodium channel.
%A Jiang D
%A Banh R
%A Gamal El-Din TM
%A Tonggu L
%A Lenaeus MJ
%A Pomès R
%A Zheng N
%A Catterall WA
%J Cell
%V 184
%N 20
%D Sep 2021 30
%M 34520724
%F 66.85
%R 10.1016/j.cell.2021.08.021
%X 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.