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- PDB-8gz1: Cryo-EM structure of human NaV1.6/beta1/beta2,apo state -

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Basic information

Entry
Database: PDB / ID: 8gz1
TitleCryo-EM structure of human NaV1.6/beta1/beta2,apo state
Components
  • (Sodium channel subunit beta- ...) x 2
  • Sodium channel protein type 8 subunit alpha
KeywordsMEMBRANE PROTEIN / ion channal
Function / homology
Function and homology information


corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / response to pyrethroid / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / membrane depolarization during Purkinje myocyte cell action potential / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / regulation of sodium ion transmembrane transporter activity / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / axon initial segment / sodium ion binding ...corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / response to pyrethroid / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / membrane depolarization during Purkinje myocyte cell action potential / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / regulation of sodium ion transmembrane transporter activity / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / axon initial segment / sodium ion binding / regulation of atrial cardiac muscle cell membrane depolarization / cardiac conduction / voltage-gated sodium channel complex / 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 / high voltage-gated calcium channel activity / locomotion / optic nerve development / voltage-gated sodium channel activity / regulation of ventricular cardiac muscle cell membrane repolarization / sodium channel inhibitor activity / neuronal action potential propagation / Interaction between L1 and Ankyrins / parallel fiber to Purkinje cell synapse / sodium ion transport / voltage-gated calcium channel complex / regulation of heart rate by cardiac conduction / Phase 0 - rapid depolarisation / calcium ion import across plasma membrane / membrane depolarization / neuronal action potential / sodium ion transmembrane transport / sodium channel regulator activity / intercalated disc / presynaptic active zone membrane / cardiac muscle contraction / T-tubule / myelination / axon guidance / postsynaptic density membrane / positive regulation of neuron projection development / Sensory perception of sweet, bitter, and umami (glutamate) taste / Z disc / cell junction / gene expression / nervous system development / response to heat / perikaryon / chemical synaptic transmission / cytoplasmic vesicle / transmembrane transporter binding / cell adhesion / axon / glutamatergic synapse / synapse / extracellular region / ATP binding / membrane / plasma membrane
Similarity search - Function
Voltage gated sodium channel, alpha-8 subunit / Sodium channel subunit beta-1/beta-3 / Myelin P0 protein-related / Voltage-gated Na+ ion channel, cytoplasmic domain / Cytoplasmic domain of voltage-gated Na+ ion channel / Voltage-gated sodium channel alpha subunit, inactivation gate / Sodium ion transport-associated / Sodium ion transport-associated / Voltage gated sodium channel, alpha subunit / IQ calmodulin-binding motif ...Voltage gated sodium channel, alpha-8 subunit / Sodium channel subunit beta-1/beta-3 / Myelin P0 protein-related / Voltage-gated Na+ ion channel, cytoplasmic domain / Cytoplasmic domain of voltage-gated Na+ ion channel / Voltage-gated sodium channel alpha subunit, inactivation gate / Sodium ion transport-associated / Sodium ion transport-associated / Voltage gated sodium channel, alpha subunit / IQ calmodulin-binding motif / Voltage-gated cation channel calcium and sodium / Short calmodulin-binding motif containing conserved Ile and Gln residues. / IQ motif profile. / IQ motif, EF-hand binding site / 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 subunit beta-2 / Sodium channel subunit beta-1 / Sodium channel protein type 8 subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsLi, Y. / Jiang, D.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32271272 China
CitationJournal: Nat Commun / Year: 2023
Title: Structure of human Na1.6 channel reveals Na selectivity and pore blockade by 4,9-anhydro-tetrodotoxin.
Authors: Yue Li / Tian Yuan / Bo Huang / Feng Zhou / Chao Peng / Xiaojing Li / Yunlong Qiu / Bei Yang / Yan Zhao / Zhuo Huang / Daohua Jiang /
Abstract: The sodium channel Na1.6 is widely expressed in neurons of the central and peripheral nervous systems, which plays a critical role in regulating neuronal excitability. Dysfunction of Na1.6 has been ...The sodium channel Na1.6 is widely expressed in neurons of the central and peripheral nervous systems, which plays a critical role in regulating neuronal excitability. Dysfunction of Na1.6 has been linked to epileptic encephalopathy, intellectual disability and movement disorders. Here we present cryo-EM structures of human Na1.6/β1/β2 alone and complexed with a guanidinium neurotoxin 4,9-anhydro-tetrodotoxin (4,9-ah-TTX), revealing molecular mechanism of Na1.6 inhibition by the blocker. The apo-form structure reveals two potential Na binding sites within the selectivity filter, suggesting a possible mechanism for Na selectivity and conductance. In the 4,9-ah-TTX bound structure, 4,9-ah-TTX binds to a pocket similar to the tetrodotoxin (TTX) binding site, which occupies the Na binding sites and completely blocks the channel. Molecular dynamics simulation results show that subtle conformational differences in the selectivity filter affect the affinity of TTX analogues. Taken together, our results provide important insights into Na1.6 structure, ion conductance, and inhibition.
History
DepositionSep 24, 2022Deposition site: PDBJ / Processing site: RCSB
Revision 1.0Mar 8, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
D: Sodium channel subunit beta-1
B: Sodium channel protein type 8 subunit alpha
C: Sodium channel subunit beta-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)278,03012
Polymers274,6093
Non-polymers3,4219
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Sodium channel subunit beta- ... , 2 types, 2 molecules DC

#1: Protein Sodium channel subunit beta-1 /


Mass: 24732.115 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SCN1B / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q07699
#3: Protein Sodium channel subunit beta-2 /


Mass: 24355.859 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SCN2B, UNQ326/PRO386 / Production host: Homo sapiens (human) / References: UniProt: O60939

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Protein / Non-polymers , 2 types, 3 molecules B

#2: Protein Sodium channel protein type 8 subunit alpha / / Sodium channel protein type VIII subunit alpha / Voltage-gated sodium channel subunit alpha Nav1.6


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) / References: UniProt: Q9UQD0
#6: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na

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Sugars , 2 types, 7 molecules

#4: Polysaccharide
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}}LINUCSPDB-CARE
#5: 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.: 2 / 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

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Details

Has ligand of interestY

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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: Structure of human voltage-gated sodium channel Nav1.6 in complex with auxiliary beta subunits
Type: COMPLEX / Entity ID: #1-#3 / 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 / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm
Image recordingElectron dose: 9.2 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19_4092: / Classification: refinement
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 41387 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00312200
ELECTRON MICROSCOPYf_angle_d0.5916531
ELECTRON MICROSCOPYf_dihedral_angle_d4.7641669
ELECTRON MICROSCOPYf_chiral_restr0.0421921
ELECTRON MICROSCOPYf_plane_restr0.0042019

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