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- PDB-7dtd: Voltage-gated sodium channel Nav1.1 and beta4 -

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Basic information

Entry
Database: PDB / ID: 7dtd
TitleVoltage-gated sodium channel Nav1.1 and beta4
Components
  • Sodium channel protein type 1 subunit alpha
  • Sodium channel subunit beta-4
KeywordsMEMBRANE PROTEIN / Voltage-gated sodium channel
Function / homology
Function and homology information


AV node cell action potential / membrane depolarization during action potential / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / regulation of sodium ion transmembrane transporter activity / voltage-gated monoatomic ion channel activity / voltage-gated sodium channel complex / membrane depolarization during cardiac muscle cell action potential / positive regulation of sodium ion transport / cardiac muscle cell action potential involved in contraction / voltage-gated sodium channel activity ...AV node cell action potential / membrane depolarization during action potential / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / regulation of sodium ion transmembrane transporter activity / voltage-gated monoatomic ion channel activity / voltage-gated sodium channel complex / membrane depolarization during cardiac muscle cell action potential / positive regulation of sodium ion transport / cardiac muscle cell action potential involved in contraction / voltage-gated sodium channel activity / regulation of ventricular cardiac muscle cell membrane repolarization / regulation of monoatomic ion transmembrane transport / Interaction between L1 and Ankyrins / sodium ion transport / regulation of heart rate by cardiac conduction / Phase 0 - rapid depolarisation / neuronal action potential / sodium ion transmembrane transport / sodium channel regulator activity / intercalated disc / detection of mechanical stimulus involved in sensory perception of pain / monoatomic cation channel activity / cardiac muscle contraction / establishment of localization in cell / Sensory perception of sweet, bitter, and umami (glutamate) taste / Z disc / transmembrane transporter binding / nuclear body / axon / nucleoplasm / plasma membrane
Similarity search - Function
Voltage gated sodium channel, alpha-1 subunit / Myelin P0 protein-related / Voltage-gated Na+ ion channel, cytoplasmic domain / Cytoplasmic domain of voltage-gated Na+ ion channel / Sodium ion transport-associated / Sodium ion transport-associated / Voltage gated sodium channel, alpha subunit / Voltage-gated cation channel calcium and sodium / Voltage-dependent channel domain superfamily / Immunoglobulin V-set domain ...Voltage gated sodium channel, alpha-1 subunit / Myelin P0 protein-related / Voltage-gated Na+ ion channel, cytoplasmic domain / Cytoplasmic domain of voltage-gated Na+ ion channel / Sodium ion transport-associated / Sodium ion transport-associated / Voltage gated sodium channel, alpha subunit / Voltage-gated cation channel calcium and sodium / Voltage-dependent channel domain superfamily / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Ion transport domain / Ion transport protein / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Sodium channel protein type 1 subunit alpha / Sodium channel subunit beta-4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsYan, N. / Pan, X. / Li, Z. / Huang, G.
Funding support China, 1items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2016YFA0500402 China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2021
Title: Comparative structural analysis of human Na1.1 and Na1.5 reveals mutational hotspots for sodium channelopathies.
Authors: Xiaojing Pan / Zhangqiang Li / Xueqin Jin / Yanyu Zhao / Gaoxingyu Huang / Xiaoshuang Huang / Zilin Shen / Yong Cao / Mengqiu Dong / Jianlin Lei / Nieng Yan /
Abstract: Among the nine subtypes of human voltage-gated sodium (Na) channels, the brain and cardiac isoforms, Na1.1 and Na1.5, each carry more than 400 missense mutations respectively associated with epilepsy ...Among the nine subtypes of human voltage-gated sodium (Na) channels, the brain and cardiac isoforms, Na1.1 and Na1.5, each carry more than 400 missense mutations respectively associated with epilepsy and cardiac disorders. High-resolution structures are required for structure-function relationship dissection of the disease variants. We report the cryo-EM structures of the full-length human Na1.1-β4 complex at 3.3 Å resolution here and the Na1.5-E1784K variant in the accompanying paper. Up to 341 and 261 disease-related missense mutations in Na1.1 and Na1.5, respectively, are resolved. Comparative structural analysis reveals several clusters of disease mutations that are common to both Na1.1 and Na1.5. Among these, the majority of mutations on the extracellular loops above the pore domain and the supporting segments for the selectivity filter may impair structural integrity, while those on the pore domain and the voltage-sensing domains mostly interfere with electromechanical coupling and fast inactivation. Our systematic structural delineation of these mutations provides important insight into their pathogenic mechanism, which will facilitate the development of precise therapeutic interventions against various sodium channelopathies.
History
DepositionJan 4, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 7, 2021Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
B: Sodium channel subunit beta-4
A: Sodium channel protein type 1 subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)260,2277
Polymers258,7972
Non-polymers1,4305
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area1330 Å2
ΔGint6 kcal/mol
Surface area66800 Å2

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Components

#1: Protein Sodium channel subunit beta-4 /


Mass: 25000.980 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SCN4B / Production host: Homo sapiens (human) / References: UniProt: Q8IWT1
#2: Protein Sodium channel protein type 1 subunit alpha / / Sodium channel protein brain I subunit alpha / Sodium channel protein type I subunit alpha / ...Sodium channel protein brain I subunit alpha / Sodium channel protein type I subunit alpha / Voltage-gated sodium channel subunit alpha Nav1.1


Mass: 233796.141 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SCN1A, NAC1, SCN1 / Production host: Homo sapiens (human) / References: UniProt: P35498
#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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H15NO6
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-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 / Comment: detergent*YM
Has ligand of interestN

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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: Voltage-gated sodium channelSodium channel / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 48 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 133127 / Symmetry type: POINT

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