+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-35197 | |||||||||
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Title | Structure of human Nav1.7 in complex with Vinpocetine | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Inhibitor complex. / MEMBRANE PROTEIN | |||||||||
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 / regulation of sodium ion transmembrane transporter activity / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / 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 / regulation of sodium ion transmembrane transporter activity / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / 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 / membrane depolarization during cardiac muscle cell action potential / positive regulation of sodium ion transport / node of Ranvier / membrane depolarization during action potential / cardiac muscle cell action potential involved in contraction / voltage-gated sodium channel complex / regulation of ventricular cardiac muscle cell membrane repolarization / locomotion / sodium channel inhibitor activity / neuronal action potential propagation / Interaction between L1 and Ankyrins / voltage-gated sodium channel activity / sodium ion transport / 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 / intercalated disc / sodium channel regulator activity / sodium ion transmembrane transport / neuronal action potential / 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 / chemical synaptic transmission / perikaryon / transmembrane transporter binding / cell adhesion / inflammatory response / axon / synapse / extracellular region / plasma membrane Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.9 Å | |||||||||
Authors | Wu QR / Yan N | |||||||||
Funding support | China, United States, 2 items
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Citation | Journal: Nat Commun / Year: 2023 Title: Structural mapping of Na1.7 antagonists. Authors: Qiurong Wu / Jian Huang / Xiao Fan / Kan Wang / Xueqin Jin / Gaoxingyu Huang / Jiaao Li / Xiaojing Pan / Nieng Yan / Abstract: Voltage-gated sodium (Na) channels are targeted by a number of widely used and investigational drugs for the treatment of epilepsy, arrhythmia, pain, and other disorders. Despite recent advances in ...Voltage-gated sodium (Na) channels are targeted by a number of widely used and investigational drugs for the treatment of epilepsy, arrhythmia, pain, and other disorders. Despite recent advances in structural elucidation of Na channels, the binding mode of most Na-targeting drugs remains unknown. Here we report high-resolution cryo-EM structures of human Na1.7 treated with drugs and lead compounds with representative chemical backbones at resolutions of 2.6-3.2 Å. A binding site beneath the intracellular gate (site BIG) accommodates carbamazepine, bupivacaine, and lacosamide. Unexpectedly, a second molecule of lacosamide plugs into the selectivity filter from the central cavity. Fenestrations are popular sites for various state-dependent drugs. We show that vinpocetine, a synthetic derivative of a vinca alkaloid, and hardwickiic acid, a natural product with antinociceptive effect, bind to the III-IV fenestration, while vixotrigine, an analgesic candidate, penetrates the IV-I fenestration of the pore domain. Our results permit building a 3D structural map for known drug-binding sites on Na channels summarized from the present and previous structures. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_35197.map.gz | 59.6 MB | EMDB map data format | |
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Header (meta data) | emd-35197-v30.xml emd-35197.xml | 20.1 KB 20.1 KB | Display Display | EMDB header |
Images | emd_35197.png | 75.4 KB | ||
Filedesc metadata | emd-35197.cif.gz | 7.7 KB | ||
Others | emd_35197_half_map_1.map.gz emd_35197_half_map_2.map.gz | 59.4 MB 59.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-35197 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-35197 | HTTPS FTP |
-Related structure data
Related structure data | 8i5xMC 8i5bC 8i5gC 8i5yC 8j4fC 8s9bC 8s9cC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_35197.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.0825 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_35197_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_35197_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
+Entire : human Nav1.7 in complex with vinpocetine
+Supramolecule #1: human Nav1.7 in complex with vinpocetine
+Macromolecule #1: Sodium channel protein type 9 subunit alpha
+Macromolecule #2: Sodium channel subunit beta-1
+Macromolecule #3: Sodium channel subunit beta-2
+Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose
+Macromolecule #6: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phospho...
+Macromolecule #7: CHOLESTEROL HEMISUCCINATE
+Macromolecule #8: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]sp...
+Macromolecule #9: Vinpocetine
+Macromolecule #10: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE
+Macromolecule #11: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.5 µm |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: EMDB MAP EMDB ID: |
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Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 304324 |