[English] 日本語
Yorodumi- PDB-8gz2: Cryo-EM structure of human NaV1.6/beta1/beta2-4,9-anhydro-tetrodotoxin -
+Open data
-Basic information
Entry | Database: PDB / ID: 8gz2 | ||||||
---|---|---|---|---|---|---|---|
Title | Cryo-EM structure of human NaV1.6/beta1/beta2-4,9-anhydro-tetrodotoxin | ||||||
Components |
| ||||||
Keywords | MEMBRANE PROTEIN / ion channal | ||||||
Function / homology | Function and homology information corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / response to pyrethroid / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / glutamine synthetase / glutamine biosynthetic process / regulation of sodium ion transmembrane transporter activity / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / glutamine synthetase activity / membrane depolarization during Purkinje myocyte cell action potential ...corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / response to pyrethroid / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / glutamine synthetase / glutamine biosynthetic process / regulation of sodium ion transmembrane transporter activity / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / glutamine synthetase activity / membrane depolarization during Purkinje myocyte cell action potential / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / regulation of atrial cardiac muscle cell membrane depolarization / cardiac conduction / membrane depolarization during cardiac muscle cell action potential / positive regulation of sodium ion transport / node of Ranvier / cardiac muscle cell action potential involved in contraction / locomotion / voltage-gated sodium channel complex / regulation of ventricular cardiac muscle cell membrane repolarization / sodium channel inhibitor activity / neuronal action potential propagation / Interaction between L1 and Ankyrins / voltage-gated sodium channel activity / Phase 0 - rapid depolarisation / regulation of heart rate by cardiac conduction / membrane depolarization / intercalated disc / sodium channel regulator activity / sodium ion transmembrane transport / cardiac muscle contraction / T-tubule / axon guidance / positive regulation of neuron projection development / Sensory perception of sweet, bitter, and umami (glutamate) taste / nervous system development / gene expression / response to heat / chemical synaptic transmission / perikaryon / transmembrane transporter binding / cell adhesion / synapse / extracellular region / ATP binding / metal ion binding / plasma membrane / cytoplasm Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å | ||||||
Authors | Li, Y. / Jiang, D. | ||||||
Funding support | China, 1items
| ||||||
Citation | Journal: Nat Commun / Year: 2023 Title: Structure of human Na1.6 channel reveals Na selectivity and pore blockade by 4,9-anhydro-tetrodotoxin. Authors: Yue Li / Tian Yuan / Bo Huang / Feng Zhou / Chao Peng / Xiaojing Li / Yunlong Qiu / Bei Yang / Yan Zhao / Zhuo Huang / Daohua Jiang / Abstract: The sodium channel Na1.6 is widely expressed in neurons of the central and peripheral nervous systems, which plays a critical role in regulating neuronal excitability. Dysfunction of Na1.6 has been ...The sodium channel Na1.6 is widely expressed in neurons of the central and peripheral nervous systems, which plays a critical role in regulating neuronal excitability. Dysfunction of Na1.6 has been linked to epileptic encephalopathy, intellectual disability and movement disorders. Here we present cryo-EM structures of human Na1.6/β1/β2 alone and complexed with a guanidinium neurotoxin 4,9-anhydro-tetrodotoxin (4,9-ah-TTX), revealing molecular mechanism of Na1.6 inhibition by the blocker. The apo-form structure reveals two potential Na binding sites within the selectivity filter, suggesting a possible mechanism for Na selectivity and conductance. In the 4,9-ah-TTX bound structure, 4,9-ah-TTX binds to a pocket similar to the tetrodotoxin (TTX) binding site, which occupies the Na binding sites and completely blocks the channel. Molecular dynamics simulation results show that subtle conformational differences in the selectivity filter affect the affinity of TTX analogues. Taken together, our results provide important insights into Na1.6 structure, ion conductance, and inhibition. | ||||||
History |
|
-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
---|
-Downloads & links
-Download
PDBx/mmCIF format | 8gz2.cif.gz | 298.7 KB | Display | PDBx/mmCIF format |
---|---|---|---|---|
PDB format | pdb8gz2.ent.gz | 230.8 KB | Display | PDB format |
PDBx/mmJSON format | 8gz2.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8gz2_validation.pdf.gz | 1.5 MB | Display | wwPDB validaton report |
---|---|---|---|---|
Full document | 8gz2_full_validation.pdf.gz | 1.5 MB | Display | |
Data in XML | 8gz2_validation.xml.gz | 52.5 KB | Display | |
Data in CIF | 8gz2_validation.cif.gz | 76.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/gz/8gz2 ftp://data.pdbj.org/pub/pdb/validation_reports/gz/8gz2 | HTTPS FTP |
-Related structure data
Related structure data | 34388MC 8gz1C M: map data used to model this data C: citing same article (ref.) |
---|---|
Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
|
---|---|
1 |
|
-Components
-Sodium channel subunit beta- ... , 2 types, 2 molecules DC
#1: Protein | Mass: 24732.115 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: SCN1B / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q07699 |
---|---|
#3: Protein | Mass: 24355.859 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: SCN2B, UNQ326/PRO386 / Production host: Homo sapiens (human) / References: UniProt: O60939 |
-Protein / Non-polymers , 2 types, 2 molecules B
#2: Protein | Mass: 225520.609 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: SCN8A, MED / Production host: Homo sapiens (human) / References: UniProt: Q9UQD0 |
---|---|
#6: Chemical | ChemComp-WMK / ( |
-Sugars , 2 types, 7 molecules
#4: 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 Source method: isolated from a genetically manipulated source #5: Sugar | |
---|
-Details
Has ligand of interest | Y |
---|
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
---|---|
EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Structure of human voltage-gated sodium channel Nav1.6 in complex with auxiliary beta subunits Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT |
---|---|
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
---|---|
Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm |
Image recording | Electron dose: 9.2 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.18.2_3874: / Classification: refinement | ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
CTF correction | Type: PHASE FLIPPING ONLY | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 76448 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
|