{Reference Type}: Journal Article
{Title}: Open-state structure and pore gating mechanism of the cardiac sodium channel.
{Author}: Jiang D;Banh R;Gamal El-Din TM;Tonggu L;Lenaeus MJ;Pomès R;Zheng N;Catterall WA;
{Journal}: Cell
{Volume}: 184
{Issue}: 20
{Year}: Sep 2021 30
{Factor}: 66.85
{DOI}: 10.1016/j.cell.2021.08.021
{Abstract}: 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.