+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-41261 | |||||||||
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Title | Cryo-EM structure of Nav1.7 with RLZ | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Cryo-EM / sodium channel / VGSC / Nav1.7 / 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 / 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 / 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 / regulation of ventricular cardiac muscle cell membrane repolarization / voltage-gated sodium channel complex / sodium channel inhibitor activity / locomotion / neuronal action potential propagation / Interaction between L1 and Ankyrins / voltage-gated sodium channel activity / sodium ion transport / Phase 0 - rapid depolarisation / behavioral response to pain / regulation of heart rate by cardiac conduction / detection of temperature stimulus involved in sensory perception of pain / membrane depolarization / intercalated disc / sodium ion transmembrane transport / sodium channel regulator activity / cardiac muscle contraction / sensory perception of pain / T-tubule / post-embryonic development / axon guidance / circadian rhythm / response to toxic substance / Sensory perception of sweet, bitter, and umami (glutamate) taste / positive regulation of neuron projection development / 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 | Fan X / Huang J / Yan N | |||||||||
Funding support | France, 1 items
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Citation | Journal: Proc Natl Acad Sci U S A / Year: 2023 Title: Dual-pocket inhibition of Na channels by the antiepileptic drug lamotrigine. Authors: Jian Huang / Xiao Fan / Xueqin Jin / Liming Teng / Nieng Yan / Abstract: Voltage-gated sodium (Na) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Na channels serve as the primary targets for several ...Voltage-gated sodium (Na) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Na channels serve as the primary targets for several classes of widely used and investigational drugs, including local anesthetics, antiepileptic drugs, antiarrhythmics, and analgesics. In this study, we present cryogenic electron microscopy (cryo-EM) structures of human Na1.7 bound to two clinical drugs, riluzole (RLZ) and lamotrigine (LTG), at resolutions of 2.9 Å and 2.7 Å, respectively. A 3D EM reconstruction of ligand-free Na1.7 was also obtained at 2.1 Å resolution. RLZ resides in the central cavity of the pore domain and is coordinated by residues from repeats III and IV. Whereas one LTG molecule also binds to the central cavity, the other is found beneath the intracellular gate, known as site BIG. Therefore, LTG, similar to lacosamide and cannabidiol, blocks Na channels via a dual-pocket mechanism. These structures, complemented with docking and mutational analyses, also explain the structure-activity relationships of the LTG-related linear 6,6 series that have been developed for improved efficacy and subtype specificity on different Na channels. Our findings reveal the molecular basis for these drugs' mechanism of action and will aid the development of novel antiepileptic and pain-relieving drugs. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_41261.map.gz | 59.4 MB | EMDB map data format | |
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Header (meta data) | emd-41261-v30.xml emd-41261.xml | 20.1 KB 20.1 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_41261_fsc.xml | 8.4 KB | Display | FSC data file |
Images | emd_41261.png | 49.5 KB | ||
Masks | emd_41261_msk_1.map | 64 MB | Mask map | |
Filedesc metadata | emd-41261.cif.gz | 7.6 KB | ||
Others | emd_41261_half_map_1.map.gz emd_41261_half_map_2.map.gz | 59.3 MB 59.3 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-41261 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-41261 | HTTPS FTP |
-Validation report
Summary document | emd_41261_validation.pdf.gz | 1.1 MB | Display | EMDB validaton report |
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Full document | emd_41261_full_validation.pdf.gz | 1.1 MB | Display | |
Data in XML | emd_41261_validation.xml.gz | 16.4 KB | Display | |
Data in CIF | emd_41261_validation.cif.gz | 21.3 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-41261 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-41261 | HTTPS FTP |
-Related structure data
Related structure data | 8thgMC 8thhC 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_41261.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: 1.036 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_41261_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: half map 1
File | emd_41261_half_map_1.map | ||||||||||||
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Annotation | half map 1 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: half map 2
File | emd_41261_half_map_2.map | ||||||||||||
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Annotation | half map 2 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
+Entire : Human voltage-gated sodium channel Nav1.7 with beta subunits
+Supramolecule #1: Human voltage-gated sodium channel Nav1.7 with beta subunits
+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: 6-(trifluoromethoxy)-1,3-benzothiazol-2-amine
+Macromolecule #7: CHOLESTEROL HEMISUCCINATE
+Macromolecule #8: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE
+Macromolecule #9: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
+Macromolecule #10: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phospho...
+Macromolecule #11: water
-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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Image recording | Film or detector model: FEI FALCON IV (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 40.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.4000000000000001 µm / Nominal defocus min: 1.2 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |