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- PDB-6agf: Structure of the human voltage-gated sodium channel Nav1.4 in com... -

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Entry
Database: PDB / ID: 6agf
TitleStructure of the human voltage-gated sodium channel Nav1.4 in complex with beta1
Components(Sodium channel ...) x 2
KeywordsMEMBRANE PROTEIN / sodium channel
Function / homologyImmunoglobulin V-set domain / Sodium channel subunit beta-1/beta-3 / Voltage gated sodium channel, alpha subunit / Ion transport domain / Voltage gated sodium channel, alpha-4 subunit, mammalian / Sodium ion transport-associated / Immunoglobulin-like fold / Voltage-dependent channel domain superfamily / Immunoglobulin-like domain superfamily / Ion transport protein ...Immunoglobulin V-set domain / Sodium channel subunit beta-1/beta-3 / Voltage gated sodium channel, alpha subunit / Ion transport domain / Voltage gated sodium channel, alpha-4 subunit, mammalian / Sodium ion transport-associated / Immunoglobulin-like fold / Voltage-dependent channel domain superfamily / Immunoglobulin-like domain superfamily / Ion transport protein / Sodium ion transport-associated / Immunoglobulin V-set domain / IQ motif profile. / Interaction between L1 and Ankyrins / Phase 0 - rapid depolarisation / IQ motif, EF-hand binding site / corticospinal neuron axon guidance / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / response to pyrethroid / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / regulation of atrial cardiac muscle cell membrane depolarization / membrane depolarization during Purkinje myocyte cell action potential / cardiac conduction / locomotion / regulation of sodium ion transmembrane transporter activity / voltage-gated sodium channel complex / cardiac muscle cell action potential involved in contraction / membrane depolarization during cardiac muscle cell action potential / regulation of ventricular cardiac muscle cell membrane repolarization / membrane depolarization during action potential / neuronal action potential propagation / node of Ranvier / positive regulation of sodium ion transport / voltage-gated sodium channel activity / sodium channel inhibitor activity / neuronal action potential / sodium ion transmembrane transport / regulation of heart rate by cardiac conduction / voltage-gated ion channel activity / sodium ion transport / membrane depolarization / intercalated disc / regulation of ion transmembrane transport / T-tubule / cardiac muscle contraction / sodium channel regulator activity / muscle contraction / positive regulation of neuron projection development / chemical synaptic transmission / axon guidance / cell adhesion / integral component of plasma membrane / extracellular region / plasma membrane / Sodium channel protein type 4 subunit alpha / Sodium channel subunit beta-1
Function and homology information
Specimen sourceHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / 3.2 Å resolution
AuthorsPan, X.J. / li, Z.Q. / Zhou, Q. / Shen, H.Z. / Wu, K. / Huang, X.S. / Chen, J.F. / Zhang, J.R. / Zhu, X.C. / Lei, J.L. / Xiong, W. / Gong, H.P. / Xiao, B.L. / Yan, N.
CitationJournal: Science / Year: 2018
Title: Structure of the human voltage-gated sodium channel Na1.4 in complex with β1.
Authors: Xiaojing Pan / Zhangqiang Li / Qiang Zhou / Huaizong Shen / Kun Wu / Xiaoshuang Huang / Jiaofeng Chen / Juanrong Zhang / Xuechen Zhu / Jianlin Lei / Wei Xiong / Haipeng Gong / Bailong Xiao / Nieng Yan
Abstract: Voltage-gated sodium (Na) channels, which are responsible for action potential generation, are implicated in many human diseases. Despite decades of rigorous characterization, the lack of a structure ...Voltage-gated sodium (Na) channels, which are responsible for action potential generation, are implicated in many human diseases. Despite decades of rigorous characterization, the lack of a structure of any human Na channel has hampered mechanistic understanding. Here, we report the cryo-electron microscopy structure of the human Na1.4-β1 complex at 3.2-Å resolution. Accurate model building was made for the pore domain, the voltage-sensing domains, and the β1 subunit, providing insight into the molecular basis for Na permeation and kinetic asymmetry of the four repeats. Structural analysis of reported functional residues and disease mutations corroborates an allosteric blocking mechanism for fast inactivation of Na channels. The structure provides a path toward mechanistic investigation of Na channels and drug discovery for Na channelopathies.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Aug 11, 2018 / Release: Oct 10, 2018

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)244,15318
Polyers237,3502
Non-polymers6,80316
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area (Å2)6030
ΔGint (kcal/M)-1
Surface area (Å2)68080

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Components

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Sodium channel ... , 2 types, 2 molecules AB

#1: Protein/peptide Sodium channel protein type 4 subunit alpha / / SkM1 / Sodium channel protein skeletal muscle subunit alpha / Sodium channel protein type IV subunit alpha / Voltage-gated sodium channel subunit alpha Nav1.4


Mass: 212643.562 Da / Num. of mol.: 1 / Source: (gene. exp.) Homo sapiens (human) / Gene: SCN4A / Production host: Homo sapiens (human) / References: UniProt: P35499
#2: Protein/peptide Sodium channel subunit beta-1 /


Mass: 24706.920 Da / Num. of mol.: 1 / Source: (gene. exp.) Homo sapiens (human) / Gene: SCN1B / Production host: Homo sapiens (human) / References: UniProt: Q07699

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Non-polymers , 4 types, 16 molecules

#3: Chemical
ChemComp-NAG / N-ACETYL-D-GLUCOSAMINE


Mass: 221.208 Da / Num. of mol.: 8 / Formula: C8H15NO6 / N-Acetylglucosamine
#4: Chemical ChemComp-BMA / BETA-D-MANNOSE


Mass: 180.156 Da / Num. of mol.: 1 / Formula: C6H12O6
#5: Chemical
ChemComp-6OU / [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate


Mass: 717.996 Da / Num. of mol.: 6 / Formula: C39H76NO8P
#6: Chemical ChemComp-9Z9 / (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en


Mass: 544.805 Da / Num. of mol.: 1 / Formula: C34H56O5

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Details

Nonpolymer detailsThe complete structure of ligand 9Z9 is glyco-diosgenin. Only partial of the molecule was modeled.

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Experimental details

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Experiment

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

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Sample preparation

Component
IDNameTypeEntity IDParent IDSource
1Complex of human sodium channel protein type 4 subunit alpha and human sodium channel subunit beta-1COMPLEX1, 20RECOMBINANT
2Human sodium channel protein type 4 subunit alphaCOMPLEX11RECOMBINANT
3Human sodium channel subunit beta-1COMPLEX21RECOMBINANT
Molecular weightValue: 0.2 MDa / Experimental value: NO
Source (natural)
IDEntity assembly IDNcbi tax IDOrganism
229606Homo sapiens (human)
339606Homo sapiens (human)
Source (recombinant)
IDEntity assembly IDNcbi tax IDOrganism
129606Homo sapiens (human)
239606Homo sapiens (human)
Buffer solutionpH: 5.9
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
MicroscopyMicroscope model: 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 K2 QUANTUM (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.13_2998: / Classification: refinement
EM software
IDNameVersionCategory
10RELION2.1initial Euler assignment
11RELION2.1final Euler assignment
12RELION2.1classification
13RELION2.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 191936 / Symmetry type: POINT

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