9P24
Structure of human cardiac sodium channel Nav1.5 in intermediate open state
Summary for 9P24
| Entry DOI | 10.2210/pdb9p24/pdb |
| EMDB information | 71158 |
| Descriptor | Sodium channel protein type 5 subunit alpha, (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total) |
| Functional Keywords | voltage gated sodium channel, nav1.5, ion transport, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 229489.61 |
| Authors | |
| Primary citation | Biswas, R.,Lopez-Serrano, A.L.,Purohit, A.,Ramirez-Navarro, A.,Huang, H.L.,Cheng, X.,Heissler, S.M.,Deschenes, I.,Chinthalapudi, K. Structural and functional mechanisms underlying activation gate dynamics and IFM motif accessibility in human Na v 1.5. Nat Commun, 17:-, 2026 Cited by PubMed Abstract: 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. PubMed: 41698958DOI: 10.1038/s41467-026-69672-x PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.48 Å) |
Structure validation
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