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- EMDB-46718: Full-length apo human voltage-gated sodium channel 1.8 (NaV1.8) -

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Basic information

Entry
Database: EMDB / ID: EMD-46718
TitleFull-length apo human voltage-gated sodium channel 1.8 (NaV1.8)
Map data
Sample
  • Complex: Sodium channel protein type 10 subunit alpha
    • Protein or peptide: Sodium channel protein type 10 subunit alpha
  • Ligand: CHOLESTEROL
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine
Keywordsion channel / MEMBRANE PROTEIN
Function / homology
Function and homology information


bundle of His cell action potential / AV node cell action potential / clathrin complex / regulation of atrial cardiac muscle cell membrane depolarization / membrane depolarization during action potential / voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / sensory perception / regulation of monoatomic ion transmembrane transport / cardiac muscle cell action potential involved in contraction / voltage-gated sodium channel complex ...bundle of His cell action potential / AV node cell action potential / clathrin complex / regulation of atrial cardiac muscle cell membrane depolarization / membrane depolarization during action potential / voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / sensory perception / regulation of monoatomic ion transmembrane transport / cardiac muscle cell action potential involved in contraction / voltage-gated sodium channel complex / Interaction between L1 and Ankyrins / voltage-gated sodium channel activity / Phase 0 - rapid depolarisation / odontogenesis of dentin-containing tooth / regulation of cardiac muscle contraction / sodium ion transmembrane transport / regulation of heart rate / presynaptic membrane / transmembrane transporter binding / axon / glutamatergic synapse / extracellular exosome / plasma membrane
Similarity search - Function
Sodium ion transport-associated / Voltage-gated sodium channel alpha subunit, inactivation gate / Sodium ion transport-associated / Voltage gated sodium channel, alpha subunit / Voltage-gated cation channel calcium and sodium / Voltage-dependent channel domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Sodium channel protein type 10 subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.12 Å
AuthorsNeumann B / McCarthy S / Gonen S
Funding support United States, 2 items
OrganizationGrant numberCountry
Department of Defense (DOD, United States)HDTRA1-21-1-0004 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35-GM142797 United States
CitationJournal: Nat Commun / Year: 2025
Title: Structural basis of inhibition of human Na1.8 by the tarantula venom peptide Protoxin-I.
Authors: Bryan Neumann / Stephen McCarthy / Shane Gonen /
Abstract: Voltage-gated sodium channels (Nas) selectively permit diffusion of sodium ions across the cell membrane and, in excitable cells, are responsible for propagating action potentials. One of the nine ...Voltage-gated sodium channels (Nas) selectively permit diffusion of sodium ions across the cell membrane and, in excitable cells, are responsible for propagating action potentials. One of the nine human Na isoforms, Na1.8, is a promising target for analgesics, and selective inhibitors are of interest as therapeutics. One such inhibitor, the gating-modifier peptide Protoxin-I derived from tarantula venom, blocks channel opening by shifting the activation voltage threshold to more depolarized potentials, but the structural basis for this inhibition has not previously been determined. Using monolayer graphene grids, we report the cryogenic electron microscopy structures of full-length human apo-Na1.8 and the Protoxin-I-bound complex at 3.1 Å and 2.8 Å resolution, respectively. The apo structure shows an unexpected movement of the Domain I S4-S5 helix, and VSD was unresolvable. We find that Protoxin-I binds to and displaces the VSD S3-S4 linker, hindering translocation of the S4 helix during activation.
History
DepositionAug 23, 2024-
Header (metadata) releaseFeb 19, 2025-
Map releaseFeb 19, 2025-
UpdateFeb 19, 2025-
Current statusFeb 19, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46718.png

Downloads & links

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Map

FileDownload / File: emd_46718.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 360 pix.
= 302.04 Å		0.84 Å/pix.
x 360 pix.
= 302.04 Å		0.84 Å/pix.
x 360 pix.
= 302.04 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.839 Å
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Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.21420287 - 0.3960556
Average (Standard dev.)0.00000498342 (±0.011901331)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 302.04 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_46718_msk_1.map
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Mask #2

Fileemd_46718_msk_2.map
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Additional map: sharpened

Fileemd_46718_additional_1.map
Annotationsharpened
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Additional map: local res

Fileemd_46718_additional_2.map
Annotationlocal res
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Additional map: filtered

Fileemd_46718_additional_3.map
Annotationfiltered
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Half map: #1

Fileemd_46718_half_map_1.map
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Half map: #2

Fileemd_46718_half_map_2.map
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Sample components

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Entire : Sodium channel protein type 10 subunit alpha

EntireName: Sodium channel protein type 10 subunit alpha
Components
  • Complex: Sodium channel protein type 10 subunit alpha
    • Protein or peptide: Sodium channel protein type 10 subunit alpha
  • Ligand: CHOLESTEROL
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine

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Supramolecule #1: Sodium channel protein type 10 subunit alpha

SupramoleculeName: Sodium channel protein type 10 subunit alpha / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Sodium channel protein type 10 subunit alpha

MacromoleculeName: Sodium channel protein type 10 subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 225.721281 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DYKDDDDKSA WSHPQFEKGG GSGGGSGGSA WSHPQFEKEN LYFQSMEFPI GSLETNNFRR FTPESLVEIE KQIAAKQGTK KAREKHREQ KDQEEKPRPQ LDLKACNQLP KFYGELPAEL IGEPLEDLDP FYSTHRTFMV LNKGRTISRF SATRALWLFS P FNLIRRTA ...String:
DYKDDDDKSA WSHPQFEKGG GSGGGSGGSA WSHPQFEKEN LYFQSMEFPI GSLETNNFRR FTPESLVEIE KQIAAKQGTK KAREKHREQ KDQEEKPRPQ LDLKACNQLP KFYGELPAEL IGEPLEDLDP FYSTHRTFMV LNKGRTISRF SATRALWLFS P FNLIRRTA IKVSVHSWFS LFITVTILVN CVCMTRTDLP EKIEYVFTVI YTFEALIKIL ARGFCLNEFT YLRDPWNWLD FS VITLAYV GTAIDLRGIS GLRTFRVLRA LKTVSVIPGL KVIVGALIHS VKKLADVTIL TIFCLSVFAL VGLQLFKGNL KNK CVKNDM AVNETTNYSS HRKPDIYINK RGTSDPLLCG NGSDSGHCPD GYICLKTSDN PDFNYTSFDS FAWAFLSLFR LMTQ DSWER LYQQTLRTSG KIYMIFFVLV IFLGSFYLVN LILAVVTMAY EEQNQATTDE IEAKEKKFQE ALEMLRKEQE VLAAL GIDT TSLHSHNGSP LTSKNASERR HRIKPRVSEG STEDNKSPRS DPYNQRRMSF LGLASGKRRA SHGSVFHFRS PGRDIS LPE GVTDDGVFPG DHESHRGSLL LGGGAGQQGP LPRSPLPQPS NPDSRHGEDE HQPPPTSELA PGAVDVSAFD AGQKKTF LS AEYLDEPFRA QRAMSVVSII TSVLEELEES EQKCPPCLTS LSQKYLIWDC CPMWVKLKTI LFGLVTDPFA ELTITLCI V VNTIFMAMEH HGMSPTFEAM LQIGNIVFTI FFTAEMVFKI IAFDPYYYFQ KKWNIFDCII VTVSLLELGV AKKGSLSVL RSFRLLRVFK LAKSWPTLNT LIKIIGNSVG ALGNLTIILA IIVFVFALVG KQLLGENYRN NRKNISAPHE DWPRWHMHDF FHSFLIVFR ILCGEWIENM WACMEVGQKS ICLILFLTVM VLGNLVVLNL FIALLLNSFS ADNLTAPEDD GEVNNLQVAL A RIQVFGHR TKQALCSFFS RSCPFPQPKA EPELVVKLPL SSSKAENHIA ANTARGSSGG LQAPRGPRDE HSDFIANPTV WV SVPIAEG ESDLDDLEDD GGEDAQSFQQ EVIPKGQQEQ LQQVERCGDH LTPRSPGTGT SSEDLAPSLG ETWKDESVPQ VPA EGVDDT SSSEGSTVDC LDPEEILRKI PELADDLEEP DDCFTEGCIR HCPCCKLDTT KSPWDVGWQV RKTCYRIVEH SWFE SFIIF MILLSSGSLA FEDYYLDQKP TVKALLEYTD RVFTFIFVFE MLLKWVAYGF KKYFTNAWCW LDFLIVNISL ISLTA KILE YSEVAPIKAL RTLRALRPLR ALSRFEGMRV VVDALVGAIP SIMNVLLVCL IFWLIFSIMG VNLFAGKFWR CINYTD GEF SLVPLSIVNN KSDCKIQNST GSFFWVNVKV NFDNVAMGYL ALLQVATFKG WMDIMYAAVD SREVNMQPKW EDNVYMY LY FVIFIIFGGF FTLNLFVGVI IDNFNQQKKK LGGQDIFMTE EQKKYYNAMK KLGSKKPQKP IPRPLNKFQG FVFDIVTR Q AFDITIMVLI CLNMITMMVE TDDQSEEKTK ILGKINQFFV AVFTGECVMK MFALRQYYFT NGWNVFDFIV VVLSIASLI FSAILKSLQS YFSPTLFRVI RLARIGRILR LIRAAKGIRT LLFALMMSLP ALFNIGLLLF LVMFIYSIFG MSSFPHVRWE AGIDDMFNF QTFANSMLCL FQITTSAGWD GLLSPILNTG PPYCDPNLPN SNGTRGDCGS PAVGIIFFTT YIIISFLIVV N MYIAVILE NFNVATEEST EPLSEDDFDM FYETWEKFDP EATQFITFSA LSDFADTLSG PLRIPKPNRN ILIQMDLPLV PG DKIHCLD ILFAFTKNVL GESGELDSLK ANMEEKFMAT NLSKSSYEPI ATTLRWKQED ISATVIQKAY RSYVLHRSMA LSN TPCVPR AEEEAASLPD EGFVAFTANE NCVLPDKSET ASATSFPPSY ESVTRGLSDR VNMRTSSSIQ NEDEATSMEL IAPG P

UniProtKB: Sodium channel protein type 10 subunit alpha

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Macromolecule #4: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 4 / Number of copies: 5 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #5: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 5 / Number of copies: 3 / Formula: PCW
Molecular weightTheoretical: 787.121 Da
Chemical component information

ChemComp-PCW:
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipid*YM

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Macromolecule #6: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 6 / Number of copies: 7 / Formula: LPE
Molecular weightTheoretical: 510.708 Da
Chemical component information

ChemComp-LPE:
1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE

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Macromolecule #7: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phospho...

MacromoleculeName: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine
type: ligand / ID: 7 / Number of copies: 2 / Formula: P5S
Molecular weightTheoretical: 792.075 Da
Chemical component information

ChemComp-P5S:
O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine

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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

Concentration0.25 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
25.0 nMHEPES
0.006 w/vGDN
GridModel: Quantifoil R2/4 / Material: GOLD / Mesh: 300 / Support film - #0 - Film type ID: 1 / Support film - #0 - Material: CARBON / Support film - #0 - topology: HOLEY / Support film - #1 - Film type ID: 2 / Support film - #1 - Material: GRAPHENE / Support film - #1 - topology: CONTINUOUS / Support film - #1 - Film thickness: 0.4 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR
Details: Negatively glow discharged with the graphene facing up
VitrificationCryogen name: ETHANE / Chamber humidity: 96 % / Chamber temperature: 283 K / Instrument: LEICA EM GP

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number real images: 13124 / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.12 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.2) / Number images used: 120821
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.2)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.2)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

7wfw

source_name: PDB, initial_model_type: experimental model

7we4

source_name: PDB, initial_model_type: experimental model
Output model

PDB-9dbk:
Full-length apo human voltage-gated sodium channel 1.8 (NaV1.8)

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