+
Open data
-
Basic information
Entry | Database: PDB / ID: 8thg | ||||||
---|---|---|---|---|---|---|---|
Title | Cryo-EM structure of Nav1.7 with RLZ | ||||||
![]() |
| ||||||
![]() | MEMBRANE PROTEIN / Cryo-EM / sodium channel / VGSC / Nav1.7 | ||||||
Function / homology | ![]() 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 / 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 | ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å | ||||||
![]() | Fan, X. / Huang, J. / Yan, N. | ||||||
Funding support | ![]()
| ||||||
![]() | ![]() 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 |
|
-
Structure visualization
Structure viewer | Molecule: ![]() ![]() |
---|
-
Downloads & links
-
Download
PDBx/mmCIF format | ![]() | 357.8 KB | Display | ![]() |
---|---|---|---|---|
PDB format | ![]() | 274.2 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
---|
-Related structure data
Related structure data | ![]() 41261MC ![]() 8thhC M: map data used to model this data C: citing same article ( |
---|---|
Similar structure data | Similarity search - Function & homology ![]() |
-
Links
-
Assembly
Deposited unit | ![]()
|
---|---|
1 |
|
-
Components
-Protein , 1 types, 1 molecules A
#1: Protein | Mass: 226620.047 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
---|
-Sodium channel subunit beta- ... , 2 types, 2 molecules BC
#2: Protein | Mass: 24732.115 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
---|---|
#3: Protein | Mass: 24355.859 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
-Sugars , 2 types, 8 molecules ![](data/chem/img/NAG.gif)
#4: Polysaccharide | Source method: isolated from a genetically manipulated source #5: Sugar | ChemComp-NAG / |
---|
-Non-polymers , 6 types, 16 molecules ![](data/chem/img/657.gif)
![](data/chem/img/Y01.gif)
![](data/chem/img/LPE.gif)
![](data/chem/img/PCW.gif)
![](data/chem/img/P5S.gif)
![](data/chem/img/HOH.gif)
![](data/chem/img/Y01.gif)
![](data/chem/img/LPE.gif)
![](data/chem/img/PCW.gif)
![](data/chem/img/P5S.gif)
![](data/chem/img/HOH.gif)
#6: Chemical | ChemComp-657 / | ||||||||
---|---|---|---|---|---|---|---|---|---|
#7: Chemical | #8: Chemical | ChemComp-LPE / #9: Chemical | ChemComp-PCW / | #10: Chemical | ChemComp-P5S / | #11: Water | ChemComp-HOH / | |
-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: Human voltage-gated sodium channel Nav1.7 with beta subunits Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT |
---|---|
Molecular weight | Experimental value: NO |
Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() |
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: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1400 nm / Nominal defocus min: 1200 nm |
Image recording | Electron dose: 40 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: FEI FALCON IV (4k x 4k) |
-
Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
3D reconstruction | Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 125461 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
|