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- PDB-6j8e: Human Nav1.2-beta2-KIIIA ternary complex -

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Entry
Database: PDB / ID: 6j8e
TitleHuman Nav1.2-beta2-KIIIA ternary complex
Components
  • (Sodium channel ...) x 2
  • Mu-conotoxin KIIIA
KeywordsMEMBRANE PROTEIN/TOXIN / transmembrane protein / MEMBRANE PROTEIN / MEMBRANE PROTEIN-TOXIN complex
Function / homologyImmunoglobulin-like fold / Voltage-dependent channel domain superfamily / Voltage gated sodium channel, alpha subunit / Immunoglobulin subtype / Ion transport domain / IQ motif, EF-hand binding site / Immunoglobulin-like domain / Sodium ion transport-associated / Immunoglobulin V-set domain / Voltage-gated Na+ ion channel, cytoplasmic domain ...Immunoglobulin-like fold / Voltage-dependent channel domain superfamily / Voltage gated sodium channel, alpha subunit / Immunoglobulin subtype / Ion transport domain / IQ motif, EF-hand binding site / Immunoglobulin-like domain / Sodium ion transport-associated / Immunoglobulin V-set domain / Voltage-gated Na+ ion channel, cytoplasmic domain / Sodium channel subunit beta-2 / Myelin P0 protein-related / Immunoglobulin-like domain superfamily / Ion transport protein / Sodium ion transport-associated / Immunoglobulin V-set domain / Cytoplasmic domain of voltage-gated Na+ ion channel / IQ motif profile. / Ig-like domain profile. / Interaction between L1 and Ankyrins / Phase 0 - rapid depolarisation / response to pyrethroid / regulation of atrial cardiac muscle cell membrane depolarization / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / sodium channel complex / regulation of sodium ion transmembrane transporter activity / cardiac muscle cell action potential involved in contraction / membrane depolarization during cardiac muscle cell action potential / voltage-gated sodium channel complex / membrane depolarization during action potential / paranode region of axon / node of Ranvier / voltage-gated sodium channel activity / neuronal action potential / intrinsic apoptotic signaling pathway in response to osmotic stress / regulation of heart rate by cardiac conduction / sodium ion transmembrane transport / sodium ion transport / voltage-gated ion channel activity / myelination / intrinsic component of plasma membrane / intercalated disc / regulation of ion transmembrane transport / T-tubule / cardiac muscle contraction / sodium channel regulator activity / integral component of presynaptic membrane / neuron apoptotic process / nervous system development / chemical synaptic transmission / toxin activity / glutamatergic synapse / axon / integral component of plasma membrane / extracellular region / plasma membrane / Sodium channel subunit beta-2 / Mu-conotoxin KIIIB / Sodium channel protein type 2 subunit alpha
Function and homology information
Specimen sourceHomo sapiens (human)
Conus kinoshitai (invertebrata)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / 3 Å resolution
AuthorsPan, X. / Li, Z. / Huang, X. / Huang, G. / Yan, N.
CitationJournal: Science / Year: 2019
Title: Molecular basis for pore blockade of human Na channel Na1.2 by the μ-conotoxin KIIIA.
Authors: Xiaojing Pan / Zhangqiang Li / Xiaoshuang Huang / Gaoxingyu Huang / Shuai Gao / Huaizong Shen / Lei Liu / Jianlin Lei / Nieng Yan
Abstract: The voltage-gated sodium channel Na1.2 is responsible for the initiation and propagation of action potentials in the central nervous system. We report the cryo-electron microscopy structure of human ...The voltage-gated sodium channel Na1.2 is responsible for the initiation and propagation of action potentials in the central nervous system. We report the cryo-electron microscopy structure of human Na1.2 bound to a peptidic pore blocker, the μ-conotoxin KIIIA, in the presence of an auxiliary subunit β2 to an overall resolution of 3.0 Å. The immunoglobulin (Ig) domain of β2 interacts with the shoulder of the pore domain through a disulfide bond. The 16-residue KIIIA interacts with the extracellular segments in repeats I to III, placing Lys7 at the entrance to the selectivity filter. Many interacting residues are specific to Na1.2, revealing a molecular basis for KIIIA specificity. The structure establishes a framework for rational design of subtype-specific blockers for Na channels.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Jan 18, 2019 / Release: Feb 27, 2019

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Assembly

Deposited unit
C: Sodium channel subunit beta-2
A: Sodium channel protein type 2 subunit alpha
D: Mu-conotoxin KIIIA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)251,25913
Polyers248,9633
Non-polymers2,29610
Water0
1


  • idetical with deposited unit
  • defined by author
  • Evidence: microscopy, SDS-PAGE and Mass-spectrometry idenitified the presence of Nav1.2 alpha subunit and the beta2 subunit. The presence of KIIIA was confirmed by electron density analysis.
  • Download structure data
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area (Å2)4760
ΔGint (kcal/M)1
Surface area (Å2)67280

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Components

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Sodium channel ... , 2 types, 2 molecules CA

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


Mass: 14267.261 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 2 subunit alpha / / HBSC II / Sodium channel protein brain II subunit alpha / Sodium channel protein type II subunit alpha / Voltage-gated sodium channel subunit alpha Nav1.2


Mass: 232800.172 Da / Num. of mol.: 1 / Source: (gene. exp.) Homo sapiens (human) / Gene: SCN2A, NAC2, SCN2A1, SCN2A2 / Production host: Homo sapiens (human) / References: UniProt: Q99250

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Protein/peptide , 1 types, 1 molecules D

#3: Protein/peptide Mu-conotoxin KIIIA


Mass: 1895.220 Da / Num. of mol.: 1 / Source: (synth.) Conus kinoshitai (invertebrata) / References: UniProt: P0C195

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Non-polymers , 4 types, 10 molecules

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


Mass: 221.208 Da / Num. of mol.: 7 / Formula: C8H15NO6 / N-Acetylglucosamine
#5: Chemical ChemComp-BMA / BETA-D-MANNOSE


Mass: 180.156 Da / Num. of mol.: 1 / Formula: C6H12O6
#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
#7: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Formula: Na / Sodium

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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
1Ternary complex of Nav1.2-beta2-KIIIACOMPLEX1, 2, 30RECOMBINANT
2Nav1.2-beta2COMPLEX1,21RECOMBINANT
3KIIIACOMPLEX1RECOMBINANT
Molecular weightValue: 252 kDa/nm / Experimental value: YES
Source (natural)
IDEntity assembly IDNcbi tax IDOrganism
129606Homo sapiens (human)
23376876Conus kinoshitai (invertebrata)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 5.9
SpecimenConc.: 1 mg/ml / Embedding 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 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 200275 / Symmetry type: POINT

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