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- PDB-6j8i: Structure of human voltage-gated sodium channel Nav1.7 in complex... -

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Entry
Database: PDB / ID: 6j8i
TitleStructure of human voltage-gated sodium channel Nav1.7 in complex with auxiliary beta subunits, ProTx-II and tetrodotoxin (Y1755 up)
Components
  • Sodium channel protein type 9 subunit alpha
  • Sodium channel subunit beta-1
  • Sodium channel subunit beta-2
KeywordsMEMBRANE PROTEIN / voltage-gated sodium channel
Function / homologySodium ion transport-associated / Voltage-dependent channel domain superfamily / IQ motif, EF-hand binding site / Myelin P0 protein-related / Voltage gated sodium channel, alpha subunit / Immunoglobulin subtype / Ion transport domain / Immunoglobulin-like domain / Immunoglobulin V-set domain / Immunoglobulin-like fold ...Sodium ion transport-associated / Voltage-dependent channel domain superfamily / IQ motif, EF-hand binding site / Myelin P0 protein-related / Voltage gated sodium channel, alpha subunit / Immunoglobulin subtype / Ion transport domain / Immunoglobulin-like domain / Immunoglobulin V-set domain / Immunoglobulin-like fold / Voltage-gated Na+ ion channel, cytoplasmic domain / Sodium channel subunit beta-1/beta-3 / Voltage gated sodium channel, alpha-9 subunit / Sodium channel subunit beta-2 / Immunoglobulin-like domain superfamily / Ion transport protein / Sodium ion transport-associated / Immunoglobulin V-set domain / Cytoplasmic domain of voltage-gated Na+ ion channel / Ig-like domain profile. / Interaction between L1 and Ankyrins / Phase 0 - rapid depolarisation / corticospinal neuron axon guidance / regulation of voltage-gated sodium channel activity / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / response to pyrethroid / regulation of atrial cardiac muscle cell membrane depolarization / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / membrane depolarization during Purkinje myocyte cell action potential / locomotion / cardiac conduction / regulation of sodium ion transmembrane transporter activity / membrane depolarization during cardiac muscle cell action potential / cardiac muscle cell action potential involved in contraction / voltage-gated sodium channel complex / membrane depolarization during action potential / regulation of ventricular cardiac muscle cell membrane repolarization / node of Ranvier / behavioral response to pain / neuronal action potential propagation / positive regulation of sodium ion transport / voltage-gated sodium channel activity / sodium channel inhibitor activity / sodium ion binding / neuronal action potential / regulation of heart rate by cardiac conduction / sodium ion transmembrane transport / sodium ion transport / voltage-gated ion channel activity / membrane depolarization / intercalated disc / regulation of ion transmembrane transport / T-tubule / cardiac muscle contraction / sodium channel regulator activity / sensory perception of pain / post-embryonic development / positive regulation of neuron projection development / response to toxic substance / nervous system development / axon guidance / chemical synaptic transmission / ion channel binding / cell adhesion / inflammatory response / axon / integral component of plasma membrane / extracellular region / plasma membrane / Sodium channel subunit beta-2 / Sodium channel subunit beta-1 / Sodium channel protein type 9 subunit alpha
Function and homology information
Specimen sourceHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / 3.2 Å resolution
AuthorsShen, H. / Liu, D. / Lei, J. / Yan, N.
CitationJournal: Science / Year: 2019
Title: Structures of human Na1.7 channel in complex with auxiliary subunits and animal toxins.
Authors: Huaizong Shen / Dongliang Liu / Kun Wu / Jianlin Lei / Nieng Yan
Abstract: Voltage-gated sodium channel Na1.7 represents a promising target for pain relief. Here we report the cryo-EM structures of the human Na1.7-β1-β2 complex bound to two combinations of pore blockers ...Voltage-gated sodium channel Na1.7 represents a promising target for pain relief. Here we report the cryo-EM structures of the human Na1.7-β1-β2 complex bound to two combinations of pore blockers and gating modifier toxins (GMTs), tetrodotoxin with Protoxin-II and saxitoxin with Huwentoxin-IV, both determined at overall resolutions of 3.2 Å. The two structures are nearly identical except for minor shifts of VSD, whose S3-S4 linker accommodates the two GMTs in a similar manner. One additional Protoxin-II sits on top of the S3-S4 linker in VSD The structures may represent an inactivated state with all four VSDs "up" and the intracellular gate closed. The structures illuminate the path toward mechanistic understanding of the function and disease of Na1.7 and establish the foundation for structure-aided development of analgesics.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Jan 19, 2019 / Release: Feb 27, 2019

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Assembly

Deposited unit
C: Sodium channel subunit beta-2
A: Sodium channel protein type 9 subunit alpha
B: Sodium channel subunit beta-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)283,05215
Polyers280,3003
Non-polymers2,75312
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area (Å2)6770
ΔGint (kcal/M)-2
Surface area (Å2)74800

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Components

#1: Protein/peptide Sodium channel subunit beta-2 /


Mass: 24355.859 Da / Num. of mol.: 1 / Source: (gene. exp.) Homo sapiens (human) / Gene: SCN2B, UNQ326/PRO386 / Production host: Homo sapiens (human) / References: UniProt: O60939
#2: Protein/peptide Sodium channel protein type 9 subunit alpha / / Neuroendocrine sodium channel / hNE-Na / Peripheral sodium channel 1 / PN1 / Sodium channel protein type IX subunit alpha / Voltage-gated sodium channel subunit alpha Nav1.7


Mass: 231211.922 Da / Num. of mol.: 1 / Source: (gene. exp.) Homo sapiens (human) / Gene: SCN9A, NENA / Production host: Homo sapiens (human) / References: UniProt: Q15858
#3: Protein/peptide Sodium channel subunit beta-1 /


Mass: 24732.115 Da / Num. of mol.: 1 / Source: (gene. exp.) Homo sapiens (human) / Gene: SCN1B / Production host: Homo sapiens (human) / References: UniProt: Q07699
#4: Chemical
ChemComp-NAG / N-ACETYL-D-GLUCOSAMINE


Mass: 221.208 Da / Num. of mol.: 11 / Formula: C8H15NO6 / N-Acetylglucosamine
#5: Chemical ChemComp-9SR / (1R,5R,6R,7R,9S,11S,12S,13S,14S)-3-amino-14-(hydroxymethyl)-8,10-dioxa-2,4-diazatetracyclo[7.3.1.1~7,11~.0~1,6~]tetradec-3-ene-5,9,12,13,14-pentol (non-preferred name) / Tetrodotoxin


Mass: 319.268 Da / Num. of mol.: 1 / Formula: C11H17N3O8 / Tetrodotoxin

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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

ComponentName: Complex of human voltage-gated sodium channel Nav1.7 with auxiliary beta subunits, ProTx-II and tetrodotoxin
Type: COMPLEX / Entity ID: 1, 2, 3 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
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: 1.11.1_2575: / Classification: refinement
EM softwareName: RELION / Version: 2.1 / Category: classification
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 263205 / Symmetry type: POINT
Refine LS restraints
Refine IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.01211025
ELECTRON MICROSCOPYf_angle_d1.25614948
ELECTRON MICROSCOPYf_dihedral_angle_d9.0216441
ELECTRON MICROSCOPYf_chiral_restr0.0631744
ELECTRON MICROSCOPYf_plane_restr0.0071809

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