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-Structure paper
タイトル | Open-state structure and pore gating mechanism of the cardiac sodium channel. |
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ジャーナル・号・ページ | Cell, Vol. 184, Issue 20, Page 5151-5162.e11, Year 2021 |
掲載日 | 2021年9月30日 |
著者 | Daohua Jiang / Richard Banh / Tamer M Gamal El-Din / Lige Tonggu / Michael J Lenaeus / Régis Pomès / Ning Zheng / William A Catterall / |
PubMed 要旨 | The heartbeat is initiated by voltage-gated sodium channel Na1.5, which opens rapidly and triggers the cardiac action potential; however, the structural basis for pore opening remains unknown. Here, ...The heartbeat is initiated by voltage-gated sodium channel Na1.5, 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. |
リンク | Cell / PubMed:34520724 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.4 Å |
構造データ | EMDB-31519, PDB-7fbs: |
化合物 | ChemComp-NAG: ChemComp-6OU: ChemComp-4Y4: ChemComp-9Z9: |
由来 |
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キーワード | MEMBRANE PROTEIN / ion channel / four-domain |