+Open data
-Basic information
Entry | Database: PDB / ID: 8fhd | ||||||
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Title | Cryo-EM structure of human voltage-gated sodium channel Nav1.6 | ||||||
Components | (Sodium channel ...) x 2 | ||||||
Keywords | MEMBRANE PROTEIN / Voltage-gated sodium channel / Nav1.6 | ||||||
Function / homology | Function and homology information corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / regulation of sodium ion transmembrane transporter activity / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / membrane depolarization during Purkinje myocyte cell action potential / axon initial segment / sodium ion binding / regulation of atrial cardiac muscle cell membrane depolarization / cardiac conduction ...corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / regulation of sodium ion transmembrane transporter activity / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / membrane depolarization during Purkinje myocyte cell action potential / axon initial segment / sodium ion binding / regulation of atrial cardiac muscle cell membrane depolarization / cardiac conduction / high voltage-gated calcium channel activity / membrane depolarization during cardiac muscle cell action potential / positive regulation of sodium ion transport / peripheral nervous system development / node of Ranvier / cardiac muscle cell action potential involved in contraction / optic nerve development / voltage-gated sodium channel complex / regulation of ventricular cardiac muscle cell membrane repolarization / locomotion / sodium channel inhibitor activity / neuronal action potential propagation / Interaction between L1 and Ankyrins / parallel fiber to Purkinje cell synapse / voltage-gated sodium channel activity / voltage-gated calcium channel complex / sodium ion transport / Phase 0 - rapid depolarisation / regulation of heart rate by cardiac conduction / membrane depolarization / calcium ion import across plasma membrane / intercalated disc / sodium channel regulator activity / sodium ion transmembrane transport / neuronal action potential / presynaptic active zone membrane / cardiac muscle contraction / T-tubule / myelination / axon guidance / postsynaptic density membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / positive regulation of neuron projection development / Z disc / cell junction / nervous system development / cytoplasmic vesicle / perikaryon / transmembrane transporter binding / cell adhesion / axon / glutamatergic synapse / extracellular region / ATP binding / membrane / plasma membrane Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å | ||||||
Authors | Fan, X. / Huang, J. / Yan, N. | ||||||
Funding support | France, 1items
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Citation | Journal: Proc Natl Acad Sci U S A / Year: 2023 Title: Cryo-EM structure of human voltage-gated sodium channel Na1.6. Authors: Xiao Fan / Jian Huang / Xueqin Jin / Nieng Yan / Abstract: Voltage-gated sodium channel Na1.6 plays a crucial role in neuronal firing in the central nervous system (CNS). Aberrant function of Na1.6 may lead to epilepsy and other neurological disorders. ...Voltage-gated sodium channel Na1.6 plays a crucial role in neuronal firing in the central nervous system (CNS). Aberrant function of Na1.6 may lead to epilepsy and other neurological disorders. Specific inhibitors of Na1.6 thus have therapeutic potentials. Here we present the cryo-EM structure of human Na1.6 in the presence of auxiliary subunits β1 and fibroblast growth factor homologous factor 2B (FHF2B) at an overall resolution of 3.1 Å. The overall structure represents an inactivated state with closed pore domain (PD) and all "up" voltage-sensing domains. A conserved carbohydrate-aromatic interaction involving Trp302 and Asn326, together with the β1 subunit, stabilizes the extracellular loop in repeat I. Apart from regular lipids that are resolved in the EM map, an unprecedented Y-shaped density that belongs to an unidentified molecule binds to the PD, revealing a potential site for developing Na1.6-specific blockers. Structural mapping of disease-related Na1.6 mutations provides insights into their pathogenic mechanism. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8fhd.cif.gz | 333.2 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8fhd.ent.gz | 265.6 KB | Display | PDB format |
PDBx/mmJSON format | 8fhd.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/fh/8fhd ftp://data.pdbj.org/pub/pdb/validation_reports/fh/8fhd | HTTPS FTP |
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-Related structure data
Related structure data | 29082MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Sodium channel ... , 2 types, 2 molecules AC
#1: Protein | Mass: 225520.609 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: SCN8A, MED / Production host: Homo sapiens (human) / Strain (production host): HEK293F / References: UniProt: Q9UQD0 |
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#2: Protein | Mass: 24732.115 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: SCN1B / Production host: Homo sapiens (human) / Strain (production host): HEK293F / References: UniProt: Q07699 |
-Sugars , 3 types, 9 molecules
#3: Polysaccharide | alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]alpha-D- ...alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose Source method: isolated from a genetically manipulated source |
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#4: Polysaccharide | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose Source method: isolated from a genetically manipulated source |
#5: Sugar | ChemComp-NAG / |
-Non-polymers , 7 types, 17 molecules
#6: Chemical | ChemComp-Y01 / #7: Chemical | ChemComp-CLR / | #8: Chemical | ChemComp-LPE / #9: Chemical | #10: Chemical | #11: Chemical | ChemComp-9Z9 / ( | #12: Chemical | ChemComp-P3X / ( | |
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-Details
Has ligand of interest | N |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Complex of human voltage-gated sodium channel Nav1.6 with auxiliary beta-1 subunit Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) / Strain: HEK293F |
Buffer solution | pH: 7.5 / Details: 25 mM Tris-HCl (pH 7.5), 150 mM NaCl and 0.02% GDN |
Specimen | Conc.: 7 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3 |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 10 K |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1500 nm / Nominal defocus min: 1200 nm / Cs: 0.01 mm |
Specimen holder | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Average exposure time: 5.6 sec. / Electron dose: 50 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 3168 |
Image scans | Sampling size: 5 µm / Width: 7676 / Height: 7420 / Movie frames/image: 32 / Used frames/image: 1-32 |
-Processing
Software | Name: PHENIX / Version: 1.20_4459: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 74103 / Num. of class averages: 1 / Symmetry type: POINT | ||||||||||||||||||||||||
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