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-Structure paper
| タイトル | Structural basis of human Na1.5 gating mechanisms. |
|---|---|
| ジャーナル・号・ページ | Proc Natl Acad Sci U S A, Vol. 122, Issue 20, Page e2416181122, Year 2025 |
| 掲載日 | 2025年5月20日 |
著者 | Rupam Biswas / Ana Laura López-Serrano / Apoorva Purohit / Angelina Ramirez-Navarro / Hsiang-Ling Huang / Giovanna Grandinetti / Xiaolin Cheng / Sarah M Heissler / Isabelle Deschênes / Krishna Chinthalapudi / ![]() |
| PubMed 要旨 | 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 ...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. |
リンク | Proc Natl Acad Sci U S A / PubMed:40366698 / PubMed Central |
| 手法 | EM (単粒子) |
| 解像度 | 3.6 - 3.9 Å |
| 構造データ | EMDB-43662, PDB-8vyj: EMDB-43663, PDB-8vyk: |
| 化合物 | ![]() ChemComp-6OU: ![]() ChemComp-Y01: ![]() ChemComp-NAG: |
| 由来 |
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キーワード | MEMBRANE PROTEIN / Voltage gated sodium channel / Nav1.5 / Ion Transporter / Ion Transport |
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