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- EMDB-9780: Molecular basis for pore blockade of human Sodium channel Nav1.2 ... -

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Basic information

Entry
Database: EMDB / ID: 9780
TitleMolecular basis for pore blockade of human Sodium channel Nav1.2 by mu-conotoxin KIIIA
Map dataThe map after postprocessing in RELION2.1.
SampleNav1.2-beta2-KIIIA
  • Nav1.2-beta2
  • KIIIA
  • Human Voltage gated sodium channel sub-type 1.2
  • Sodium channel protein type 2 subunit alpha
  • Mu-conotoxin KIIIA
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 / sodium ion transmembrane transport / regulation of heart rate by cardiac conduction / 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
SourceHomo sapiens (human) / Conus kinoshitai (invertebrata)
Methodsingle particle reconstruction / cryo EM / 3 Å resolution
AuthorsPan X / Li Z / Huang X / Huang G / Shen H / Lei J / 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 angstroms. The immunoglobulin 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 Lys 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 the rational design of subtype-specific blockers for Na channels.
Validation ReportPDB-ID: 6j8e

SummaryFull reportAbout validation report
DateDeposition: Jan 18, 2019 / Header (metadata) release: Feb 27, 2019 / Map release: Feb 27, 2019 / Last update: Feb 27, 2019

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.05
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.05
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: : PDB-6j8e
  • Surface level: 0.05
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

Fileemd_9780.map.gz (map file in CCP4 format, 55297 KB)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
240 pix
1.09 Å/pix.
= 261.84 Å
240 pix
1.09 Å/pix.
= 261.84 Å
240 pix
1.09 Å/pix.
= 261.84 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.091 Å
Density
Contour Level:0.05 (by author), 0.05 (movie #1):
Minimum - Maximum-0.13213122 - 0.28682157
Average (Standard dev.)0.0005159385 (0.00825877)
Details

EMDB XML:

Space Group Number1
Map Geometry
Axis orderXYZ
Dimensions240240240
Origin0.00.00.0
Limit239.0239.0239.0
Spacing240240240
CellA=B=C: 261.84 Å
α=β=γ: 90.0 deg.

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0911.0911.091
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z261.840261.840261.840
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ364364364
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS240240240
D min/max/mean-0.1320.2870.001

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Supplemental data

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Sample components

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Entire Nav1.2-beta2-KIIIA

EntireName: Nav1.2-beta2-KIIIA
Details: Ternary complex of Human Nav1.2 with Human Voltage-gated sodium channel auxilliary subunit beta2 and mu-conotoxin KIIIA
Number of components: 6

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Component #1: protein, Nav1.2-beta2-KIIIA

ProteinName: Nav1.2-beta2-KIIIA
Details: Ternary complex of Human Nav1.2 with Human Voltage-gated sodium channel auxilliary subunit beta2 and mu-conotoxin KIIIA
Recombinant expression: No
MassExperimental: 252 MDa

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Component #2: protein, Nav1.2-beta2

ProteinName: Nav1.2-beta2
Details: Human Nav1.2 with Human Voltage-gated sodium channel auxilliary subunit beta2
Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #3: protein, KIIIA

ProteinName: KIIIA / Details: mu-conotoxin KIIIA / Recombinant expression: No
SourceSpecies: Conus kinoshitai (invertebrata)

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Component #4: protein, Human Voltage gated sodium channel sub-type 1.2

ProteinName: Human Voltage gated sodium channel sub-type 1.2 / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #5: protein, Sodium channel protein type 2 subunit alpha

ProteinName: Sodium channel protein type 2 subunit alpha / Recombinant expression: No
SourceSpecies: Homo sapiens (human)

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Component #6: protein, Mu-conotoxin KIIIA

ProteinName: Mu-conotoxin KIIIA / Recombinant expression: No
SourceSpecies: Conus kinoshitai (invertebrata)

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Experimental details

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Sample preparation

SpecimenSpecimen state: particle / Method: cryo EM
Sample solutionSpecimen conc.: 1 mg/ml / pH: 5.9
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 48 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 QUANTUM (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Number of projections: 200275
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Modeling #1Refinement protocol: rigid body
Output model

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