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

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Basic information

Entry
Database: PDB / ID: 9dbm
TitleFull-length apo human voltage-gated sodium channel 1.8 (NaV1.8), class II
ComponentsSodium channel protein type 10 subunit alpha
KeywordsMEMBRANE PROTEIN / ion channel
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
SCN5A-like, C-terminal IQ motif / 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
CHOLESTEROL / 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE / Chem-P5S / 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / Sodium channel protein type 10 subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.22 Å
AuthorsNeumann, B. / McCarthy, S. / Gonen, S.
Funding support United States, 2items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 19, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Sodium channel protein type 10 subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)237,59722
Polymers225,7211
Non-polymers11,87621
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein / Sugars , 2 types, 6 molecules A

#1: Protein Sodium channel protein type 10 subunit alpha / Peripheral nerve sodium channel 3 / PN3 / hPN3 / Sodium channel protein type X subunit alpha / ...Peripheral nerve sodium channel 3 / PN3 / hPN3 / Sodium channel protein type X subunit alpha / Voltage-gated sodium channel subunit alpha Nav1.8


Mass: 225721.281 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SCN10A / Production host: Homo sapiens (human) / References: UniProt: Q9Y5Y9
#2: 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-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE

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Non-polymers , 4 types, 16 molecules

#3: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C27H46O
#4: Chemical ChemComp-PCW / 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / (Z,Z)-4-HYDROXY-N,N,N-TRIMETHYL-10-OXO-7-[(1-OXO-9-OCTADECENYL)OXY]-3,5,9-TRIOXA-4-PHOSPHAHEPTACOS-18-EN-1-AMINIUM-4-OXIDE


Mass: 787.121 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C44H85NO8P / Comment: DOPC, phospholipid*YM
#5: Chemical
ChemComp-LPE / 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE / LPC-ETHER


Mass: 510.708 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C26H57NO6P
#6: Chemical ChemComp-P5S / O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine / phosphatidyl serine


Mass: 792.075 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C42H82NO10P

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Details

Has ligand of interestN
Has protein modificationY

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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: Sodium channel protein type 10 subunit alpha / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
225 nMHEPES1
30.006 w/vGDN1
SpecimenConc.: 0.25 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: negatively glow discharged with the graphene facing up
Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/4
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 96 % / Chamber temperature: 283 K

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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 FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of real images: 13124
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.2particle selection
2SerialEMimage acquisition
4cryoSPARC4.2CTF correction
7UCSF ChimeraXmodel fitting
9cryoSPARC4.2initial Euler assignment
10cryoSPARC4.2final Euler assignment
12cryoSPARC4.23D reconstruction
13PHENIXmodel refinement
14Cootmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.22 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 82542 / Symmetry type: POINT
Atomic model buildingDetails: The initial model consisted of one of our earlier apo models.
Source name: Other / Type: experimental model

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