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- EMDB-30851: Voltage-gated sodium channel Nav1.1 and beta4 -

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Basic information

Entry
Database: EMDB / ID: EMD-30851
TitleVoltage-gated sodium channel Nav1.1 and beta4
Map datavoltage-gated sodium channelSodium channel
Sample
  • Complex: Voltage-gated sodium channelSodium channel
    • Protein or peptide: Sodium channel subunit beta-4
    • Protein or peptide: Sodium channel protein type 1 subunit alpha
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsYan N / Pan X / Li Z / Huang G
Funding support China, 1 items
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, 2021-
Header (metadata) releaseApr 7, 2021-
Map releaseApr 7, 2021-
UpdateApr 7, 2021-
Current statusApr 7, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7dtd
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30851.png

Downloads & links

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Map

FileDownload / File: emd_30851.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationvoltage-gated sodium channel
Voxel sizeX=Y=Z: 1.0979 Å
Density
Contour LevelBy AUTHOR: 0.017 / Movie #1: 0.02
Minimum - Maximum-0.08521426 - 0.16246283
Average (Standard dev.)0.0005779475 (±0.005417547)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 219.58 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.09791.09791.0979
M x/y/z200200200
origin x/y/z0.0000.0000.000
length x/y/z219.580219.580219.580
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ160160160
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS200200200
D min/max/mean-0.0850.1620.001

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Supplemental data

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Sample components

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Entire : Voltage-gated sodium channel

EntireName: Voltage-gated sodium channelSodium channel
Components
  • Complex: Voltage-gated sodium channelSodium channel
    • Protein or peptide: Sodium channel subunit beta-4
    • Protein or peptide: Sodium channel protein type 1 subunit alpha
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en

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Supramolecule #1: Voltage-gated sodium channel

SupramoleculeName: Voltage-gated sodium channel / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: Sodium channel subunit beta-4

MacromoleculeName: Sodium channel subunit beta-4 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.00098 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPGAGDGGKA PARWLGTGLL GLFLLPVTLS LEVSVGKATD IYAVNGTEIL LPCTFSSCFG FEDLHFRWTY NSSDAFKILI EGTVKNEKS DPKVTLKDDD RITLVGSTKE KMNNISIVLR DLEFSDTGKY TCHVKNPKEN NLQHHATIFL QVVDRLEEVD N TVTLIILA ...String:
MPGAGDGGKA PARWLGTGLL GLFLLPVTLS LEVSVGKATD IYAVNGTEIL LPCTFSSCFG FEDLHFRWTY NSSDAFKILI EGTVKNEKS DPKVTLKDDD RITLVGSTKE KMNNISIVLR DLEFSDTGKY TCHVKNPKEN NLQHHATIFL QVVDRLEEVD N TVTLIILA VVGGVIGLLI LILLIKKLII FILKKTREKK KECLVSSSGN DNTENGLPGS KAEEKPPSKV

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Macromolecule #2: Sodium channel protein type 1 subunit alpha

MacromoleculeName: Sodium channel protein type 1 subunit alpha / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 233.796141 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MASWSHPQFE KGGGARGGSG GGSWSHPQFE KGFDYKDDDD KGTMEQTVLV PPGPDSFNFF TRESLAAIER RIAEEKAKNP KPDKKDDDE NGPKPNSDLE AGKNLPFIYG DIPPEMVSEP LEDLDPYYIN KKTFIVLNKG KAIFRFSATS ALYILTPFNP L RKIAIKIL ...String:
MASWSHPQFE KGGGARGGSG GGSWSHPQFE KGFDYKDDDD KGTMEQTVLV PPGPDSFNFF TRESLAAIER RIAEEKAKNP KPDKKDDDE NGPKPNSDLE AGKNLPFIYG DIPPEMVSEP LEDLDPYYIN KKTFIVLNKG KAIFRFSATS ALYILTPFNP L RKIAIKIL VHSLFSMLIM CTILTNCVFM TMSNPPDWTK NVEYTFTGIY TFESLIKIIA RGFCLEDFTF LRDPWNWLDF TV ITFAYVT EFVDLGNVSA LRTFRVLRAL KTISVIPGLK TIVGALIQSV KKLSDVMILT VFCLSVFALI GLQLFMGNLR NKC IQWPPT NASLEEHSIE KNITVNYNGT LINETVFEFD WKSYIQDSRY HYFLEGFLDA LLCGNSSDAG QCPEGYMCVK AGRN PNYGY TSFDTFSWAF LSLFRLMTQD FWENLYQLTL RAAGKTYMIF FVLVIFLGSF YLINLILAVV AMAYEEQNQA TLEEA EQKE AEFQQMIEQL KKQQEAAQQA ATATASEHSR EPSAAGRLSD SSSEASKLSS KSAKERRNRR KKRKQKEQSG GEEKDE DEF QKSESEDSIR RKGFRFSIEG NRLTYEKRYS SPHQSLLSIR GSLFSPRRNS RTSLFSFRGR AKDVGSENDF ADDEHST FE DNESRRDSLF VPRRHGERRN SNLSQTSRSS RMLAVFPANG KMHSTVDCNG VVSLVGGPSV PTSPVGQLLP EVIIDKPA T DDNGTTTETE MRKRRSSSFH VSMDFLEDPS QRQRAMSIAS ILTNTVEELE ESRQKCPPCW YKFSNIFLIW DCSPYWLKV KHVVNLVVMD PFVDLAITIC IVLNTLFMAM EHYPMTDHFN NVLTVGNLVF TGIFTAEMFL KIIAMDPYYY FQEGWNIFDG FIVTLSLVE LGLANVEGLS VLRSFRLLRV FKLAKSWPTL NMLIKIIGNS VGALGNLTLV LAIIVFIFAV VGMQLFGKSY K DCVCKIAS DCQLPRWHMN DFFHSFLIVF RVLCGEWIET MWDCMEVAGQ AMCLTVFMMV MVIGNLVVLN LFLALLLSSF SA DNLAATD DDNEMNNLQI AVDRMHKGVA YVKRKIYEFI QQSFIRKQKI LDEIKPLDDL NNKKDSCMSN HTAEIGKDLD YLK DVNGTT SGIGTGSSVE KYIIDESDYM SFINNPSLTV TVPIAVGESD FENLNTEDFS SESDLEESKE KLNESSSSSE GSTV DIGAP VEEQPVVEPE ETLEPEACFT EGCVQRFKCC QINVEEGRGK QWWNLRRTCF RIVEHNWFET FIVFMILLSS GALAF EDIY IDQRKTIKTM LEYADKVFTY IFILEMLLKW VAYGYQTYFT NAWCWLDFLI VDVSLVSLTA NALGYSELGA IKSLRT LRA LRPLRALSRF EGMRVVVNAL LGAIPSIMNV LLVCLIFWLI FSIMGVNLFA GKFYHCINTT TGDRFDIEDV NNHTDCL KL IERNETARWK NVKVNFDNVG FGYLSLLQVA TFKGWMDIMY AAVDSRNVEL QPKYEESLYM YLYFVIFIIF GSFFTLNL F IGVIIDNFNQ QKKKFGGQDI FMTEEQKKYY NAMKKLGSKK PQKPIPRPGN KFQGMVFDFV TRQVFDISIM ILICLNMVT MMVETDDQSE YVTTILSRIN LVFIVLFTGE CVLKLISLRH YYFTIGWNIF DFVVVILSIV GMFLAELIEK YFVSPTLFRV IRLARIGRI LRLIKGAKGI RTLLFALMMS LPALFNIGLL LFLVMFIYAI FGMSNFAYVK REVGIDDMFN FETFGNSMIC L FQITTSAG WDGLLAPILN SKPPDCDPNK VNPGSSVKGD CGNPSVGIFF FVSYIIISFL VVVNMYIAVI LENFSVATEE SA EPLSEDD FEMFYEVWEK FDPDATQFME FEKLSQFAAA LEPPLNLPQP NKLQLIAMDL PMVSGDRIHC LDILFAFTKR VLG ESGEMD ALRIQMEERF MASNPSKVSY QPITTTLKRK QEEVSAVIIQ RAYRRHLLKR TVKQASFTYN KNKIKGGANL LIKE DMIID RINENSITEK TDLTMSTAAC PPSYDRVTKP IVEKHEQEGK DEKAKGK

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 4 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Macromolecule #4: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]sp...

MacromoleculeName: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en
type: ligand / ID: 4 / Number of copies: 1 / Formula: 9Z9
Molecular weightTheoretical: 544.805 Da
Chemical component information

ChemComp-9Z9:
(3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en / detergent*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 48.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 133127

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