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- PDB-9p24: Structure of human cardiac sodium channel Nav1.5 in intermediate ... -

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Basic information

Entry
Database: PDB / ID: 9p24
TitleStructure of human cardiac sodium channel Nav1.5 in intermediate open state
ComponentsSodium channel protein type 5 subunit alpha
KeywordsMEMBRANE PROTEIN / Voltage gated sodium channel / Nav1.5 / Ion Transport
Function / homology
Function and homology information


voltage-gated sodium channel activity involved in AV node cell action potential / voltage-gated sodium channel activity involved in bundle of His cell action potential / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / voltage-gated sodium channel activity involved in SA node cell action potential / bundle of His cell action potential / regulation of ventricular cardiac muscle cell membrane depolarization / AV node cell action potential / SA node cell action potential / AV node cell to bundle of His cell communication / membrane depolarization during SA node cell action potential ...voltage-gated sodium channel activity involved in AV node cell action potential / voltage-gated sodium channel activity involved in bundle of His cell action potential / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / voltage-gated sodium channel activity involved in SA node cell action potential / bundle of His cell action potential / regulation of ventricular cardiac muscle cell membrane depolarization / AV node cell action potential / SA node cell action potential / AV node cell to bundle of His cell communication / membrane depolarization during SA node cell action potential / response to denervation involved in regulation of muscle adaptation / membrane depolarization during atrial cardiac muscle cell action potential / regulation of atrial cardiac muscle cell membrane repolarization / cardiac ventricle development / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / brainstem development / membrane depolarization during AV node cell action potential / regulation of atrial cardiac muscle cell membrane depolarization / membrane depolarization during bundle of His cell action potential / positive regulation of action potential / atrial cardiac muscle cell action potential / membrane depolarization during Purkinje myocyte cell action potential / cardiac conduction system development / telencephalon development / membrane depolarization during cardiac muscle cell action potential / positive regulation of sodium ion transport / membrane depolarization during action potential / regulation of sodium ion transmembrane transport / ventricular cardiac muscle cell action potential / regulation of ventricular cardiac muscle cell membrane repolarization / cardiac muscle cell action potential involved in contraction / voltage-gated sodium channel complex / regulation of cardiac muscle cell contraction / Interaction between L1 and Ankyrins / voltage-gated sodium channel activity / ankyrin binding / odontogenesis of dentin-containing tooth / sodium ion transport / Phase 0 - rapid depolarisation / regulation of heart rate by cardiac conduction / fibroblast growth factor binding / nitric-oxide synthase binding / intercalated disc / lateral plasma membrane / membrane depolarization / cardiac muscle contraction / T-tubule / regulation of heart rate / cellular response to calcium ion / cerebellum development / positive regulation of epithelial cell proliferation / sodium ion transmembrane transport / sarcolemma / caveola / Z disc / scaffold protein binding / transmembrane transporter binding / calmodulin binding / protein domain specific binding / ubiquitin protein ligase binding / protein kinase binding / nucleolus / perinuclear region of cytoplasm / enzyme binding / cell surface / endoplasmic reticulum / nucleoplasm / membrane / plasma membrane
Similarity search - Function
Voltage gated sodium channel, alpha-5 subunit / Voltage-gated Na+ ion channel, cytoplasmic domain / Cytoplasmic domain of voltage-gated Na+ ion channel / Sodium ion transport-associated / Voltage-gated sodium channel alpha subunit, inactivation gate / : / Sodium ion transport-associated / SCN5A-like, C-terminal IQ motif / Voltage gated sodium channel, alpha subunit / Voltage-gated cation channel calcium and sodium ...Voltage gated sodium channel, alpha-5 subunit / Voltage-gated Na+ ion channel, cytoplasmic domain / Cytoplasmic domain of voltage-gated Na+ ion channel / Sodium ion transport-associated / Voltage-gated sodium channel alpha subunit, inactivation gate / : / Sodium ion transport-associated / SCN5A-like, C-terminal IQ motif / Voltage gated sodium channel, alpha subunit / Voltage-gated cation channel calcium and sodium / Voltage-dependent channel domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Sodium channel protein type 5 subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.48 Å
AuthorsBiswas, R. / Chinthalapudi, K.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL094450 United States
CitationJournal: Nat Commun / Year: 2026
Title: Structural and functional mechanisms underlying activation gate dynamics and IFM motif accessibility in human Na1.5.
Authors: Rupam Biswas / Ana Laura López-Serrano / Apoorva Purohit / Angelina Ramirez-Navarro / Hsiang-Ling Huang / Xiaolin Cheng / Sarah M Heissler / Isabelle Deschênes / Krishna Chinthalapudi /
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 ...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.
History
DepositionJun 11, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 8, 2026Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Sodium channel protein type 5 subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)229,49011
Polymers227,1521
Non-polymers2,33710
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Sodium channel protein type 5 subunit alpha / Sodium channel protein cardiac muscle subunit alpha / Sodium channel protein type V subunit alpha / ...Sodium channel protein cardiac muscle subunit alpha / Sodium channel protein type V subunit alpha / Voltage-gated sodium channel subunit alpha Nav1.5 / hH1


Mass: 227152.156 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SCN5A / Production host: Homo sapiens (human) / References: UniProt: Q14524
#2: Chemical ChemComp-9Z9 / (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en


Mass: 544.805 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H56O5 / Feature type: SUBJECT OF INVESTIGATION / Comment: detergent*YM
#3: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Sodium channel protein type 5 subunit alpha / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.2269 MDa / Experimental value: NO
Source (natural)Organism: Mammalia (mammals)
Source (recombinant)Organism: Mammalia (mammals)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: UltrAuFoil R1.2/1.3
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameCategory
2EPUimage acquisition
9PHENIXmodel refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.48 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 90155 / Symmetry type: POINT
RefinementHighest resolution: 3.48 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00410500
ELECTRON MICROSCOPYf_angle_d0.69414240
ELECTRON MICROSCOPYf_dihedral_angle_d5.5031438
ELECTRON MICROSCOPYf_chiral_restr0.0471658
ELECTRON MICROSCOPYf_plane_restr0.0051732

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