8VYK

Structure of full-length human cardiac sodium channel - Class-II.

8VYK の概要

• エントリーDOI: 10.2210/pdb8vyk/pdb
• EMDBエントリー: 43663
• 分子名称: Sodium channel protein type 5 subunit alpha, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• 機能のキーワード: voltage gated sodium channel, nav1.5, ion transport, membrane protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 234966.04

構造登録者

Biswas, R.,Chinthalapudi, K. (登録日: 2024-02-08, 公開日: 2025-02-12, 最終更新日: 2026-02-25)

主引用文献

Biswas, R.,Lopez-Serrano, A.L.,Purohit, A.,Ramirez-Navarro, A.,Huang, H.L.,Grandinetti, G.,Cheng, X.,Heissler, S.M.,Deschenes, I.,Chinthalapudi, K.
Structural basis of human Na v 1.5 gating mechanisms.
Proc.Natl.Acad.Sci.USA, 122:e2416181122-e2416181122, 2025

PubMed Abstract: Voltage-gated Na1.5 channels are central to the generation and propagation of cardiac action potentials. Aberrations in their function are associated with a wide spectrum of cardiac diseases including arrhythmias and heart failure. Despite decades of progress in Na1.5 biology, the lack of structural insights into intracellular regions has hampered our understanding of its gating mechanisms. Here, we present two cryo-EM structures of human Na1.5 in open states, revealing sequential conformational changes in gating charges of the voltage-sensing domains (VSDs) and several intracellular regions. Despite the channel being in the open state, these structures show repositioning, but no dislodging of the IFM motif in the receptor site. Molecular dynamics analyses show our structures with CTD conduct Na ions. Notably, our structural findings highlight a dynamic C-terminal domain (CTD) and III-IV linker interaction, which regulates the conformation of VSDs and pore opening. Electrophysiological studies confirm that disrupting this interaction alters fast inactivation of Na1.5. Together, our structure-function studies establish a foundation for understanding the gating mechanisms of Na1.5 and the mechanisms underlying CTD-related channelopathies.

PubMed: 40366698
DOI: 10.1073/pnas.2416181122

実験手法

ELECTRON MICROSCOPY (3.9 Å)