+Open data
-Basic information
Entry | Database: PDB / ID: 7xm9 | ||||||
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Title | Cryo-EM structure of human NaV1.7/beta1/beta2-XEN907 | ||||||
Components |
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Keywords | TRANSPORT PROTEIN / Sodium channel | ||||||
Function / homology | Function and homology information corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / response to pyrethroid / detection of mechanical stimulus involved in sensory perception / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / regulation of sodium ion transmembrane transporter activity / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / membrane depolarization during Purkinje myocyte cell action potential / regulation of atrial cardiac muscle cell membrane depolarization ...corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / response to pyrethroid / detection of mechanical stimulus involved in sensory perception / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / regulation of sodium ion transmembrane transporter activity / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / membrane depolarization during Purkinje myocyte cell action potential / regulation of atrial cardiac muscle cell membrane depolarization / cardiac conduction / voltage-gated sodium channel complex / 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 / high voltage-gated calcium channel activity / locomotion / voltage-gated sodium channel activity / regulation of ventricular cardiac muscle cell membrane repolarization / sodium channel inhibitor activity / neuronal action potential propagation / Interaction between L1 and Ankyrins / sodium ion transport / voltage-gated calcium channel complex / behavioral response to pain / Phase 0 - rapid depolarisation / regulation of heart rate by cardiac conduction / membrane depolarization / detection of temperature stimulus involved in sensory perception of pain / calcium ion import across plasma membrane / intercalated disc / sodium channel regulator activity / sodium ion transmembrane transport / cardiac muscle contraction / sensory perception of pain / T-tubule / post-embryonic development / axon guidance / response to toxic substance / Sensory perception of sweet, bitter, and umami (glutamate) taste / positive regulation of neuron projection development / circadian rhythm / nervous system development / gene expression / response to heat / perikaryon / chemical synaptic transmission / transmembrane transporter binding / cell adhesion / inflammatory response / axon / synapse / extracellular region / plasma membrane Similarity search - Function | ||||||
Biological species | Homo sapiens (human) Aequorea victoria (jellyfish) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.22 Å | ||||||
Authors | zhang, J.T. / Jiang, D.H. | ||||||
Funding support | China, 1items
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Citation | Journal: Nat Struct Mol Biol / Year: 2022 Title: Structural basis for Na1.7 inhibition by pore blockers. Authors: Jiangtao Zhang / Yiqiang Shi / Zhuo Huang / Yue Li / Bei Yang / Jianke Gong / Daohua Jiang / Abstract: Voltage-gated sodium channel Na1.7 plays essential roles in pain and odor perception. Na1.7 variants cause pain disorders. Accordingly, Na1.7 has elicited extensive attention in developing new ...Voltage-gated sodium channel Na1.7 plays essential roles in pain and odor perception. Na1.7 variants cause pain disorders. Accordingly, Na1.7 has elicited extensive attention in developing new analgesics. Here we present cryo-EM structures of human Na1.7/β1/β2 complexed with inhibitors XEN907, TC-N1752 and Na1.7-IN2, explaining specific binding sites and modulation mechanism for the pore blockers. These inhibitors bind in the central cavity blocking ion permeation, but engage different parts of the cavity wall. XEN907 directly causes α- to π-helix transition of DIV-S6 helix, which tightens the fast inactivation gate. TC-N1752 induces π-helix transition of DII-S6 helix mediated by a conserved asparagine on DIII-S6, which closes the activation gate. Na1.7-IN2 serves as a pore blocker without causing conformational change. Electrophysiological results demonstrate that XEN907 and TC-N1752 stabilize Na1.7 in inactivated state and delay the recovery from inactivation. Our results provide structural framework for Na1.7 modulation by pore blockers, and important implications for developing subtype-selective analgesics. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7xm9.cif.gz | 340.2 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7xm9.ent.gz | 258.4 KB | Display | PDB format |
PDBx/mmJSON format | 7xm9.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/xm/7xm9 ftp://data.pdbj.org/pub/pdb/validation_reports/xm/7xm9 | HTTPS FTP |
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-Related structure data
Related structure data | 33292MC 7xmfC 7xmgC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 1 types, 1 molecules A
#1: Protein | Mass: 255679.906 Da / Num. of mol.: 1 / Mutation: W1150R Source method: isolated from a genetically manipulated source Details: The fusion protein of Sodium channel, linker, GFP, and tag. Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Aequorea victoria (jellyfish) Gene: SCN9A, NENA, gfp / Production host: Homo sapiens (human) / References: UniProt: Q15858 |
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-Sodium channel subunit beta- ... , 2 types, 2 molecules BC
#2: Protein | Mass: 54472.129 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Details: The fusion protein of Beta1, linker, GFP, and tag. Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Aequorea victoria (jellyfish) Gene: SCN1B, gfp / Production host: Homo sapiens (human) / References: UniProt: Q07699 |
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#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 / Production host: Homo sapiens (human) / References: UniProt: O60939 |
-Sugars , 2 types, 7 molecules
#4: Polysaccharide | Source method: isolated from a genetically manipulated source #5: Sugar | ChemComp-NAG / |
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-Non-polymers , 2 types, 2 molecules
#6: Chemical | ChemComp-G2E / ( |
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#7: Chemical | ChemComp-6OU / [( |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: sodium channel complex / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT |
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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 |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2500 nm / Nominal defocus min: 1200 nm |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K2 IS (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.17.1_3660: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.22 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 175883 / Symmetry type: POINT | ||||||||||||||||||||||||
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