부산대학교 도서관

Keywords cardiac sodium channel; open state; fast inactivation; arrhythmia mutation; antiarrhythmic drug; cryo-EM structure Highlights * Mutation of the fast inactivation gate IFM motif allows stable opening of the pore * The intracellular activation gate opens to ~10 Å, sufficient to conduct hydrated Na.sup.+ * Molecular dynamics analysis reveals Na.sup.+ conductance at approximately physiological rates * The antiarrhythmic drug propafenone binds the open state tightly and blocks the pore Summary The heartbeat is initiated by voltage-gated sodium channel Na.sub.V1.5, 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.sup.+ 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.