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TitleStructural and functional mechanisms underlying activation gate dynamics and IFM motif accessibility in human Na1.5.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Year 2026
Publish dateFeb 16, 2026
AuthorsRupam Biswas / Ana Laura López-Serrano / Apoorva Purohit / Angelina Ramirez-Navarro / Hsiang-Ling Huang / Xiaolin Cheng / Sarah M Heissler / Isabelle Deschênes / Krishna Chinthalapudi /
PubMed AbstractVoltage-gated sodium channels are vital for regulating excitability in muscle and nerve cells, and their dysregulation is linked to a range of diseases. However, therapeutic targeting of Na channels ...Voltage-gated sodium channels are vital for regulating excitability in muscle and nerve cells, and their dysregulation is linked to a range of diseases. However, therapeutic targeting of Na channels remains challenging due to a limited understanding of their gating mechanisms. Here, we present a cryo-EM structure of human Na1.5 in an intermediate open state, stabilized by interactions between the N-terminal domain and the S6 segment. This structure reveals a possible Na binding site adjacent to the conserved inactivation (IFM) motif. Molecular dynamics simulations demonstrate that monovalent cations stably occupy this site, while electrophysiological recordings demonstrate that ion binding modulates IFM motif docking and fast inactivation kinetics. Our findings reveal that IFM accessibility is dynamically regulated in this intermediate state, refining the canonical door-wedge model of fast inactivation. Collectively, our study provides a revised structural framework for Na1.5 gating mechanisms, suggesting an alternative pathway for ion accessibility that may inform better mechanistic and therapeutic strategies for treating Na1.5-related cardiac arrhythmias.
External linksNat Commun / PubMed:41698958 / PubMed Central
MethodsEM (single particle)
Resolution3.48 Å
Structure data

EMDB-71158, PDB-9p24:
Structure of human cardiac sodium channel Nav1.5 in intermediate open state
Method: EM (single particle) / Resolution: 3.48 Å

Chemicals

ChemComp-9Z9:
(3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en / detergent*YM

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-NA:
Unknown entry

Source
  • Mammalia (mammals)
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Voltage gated sodium channel / Nav1.5 / Ion Transport

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