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- PDB-8thh: Cryo-EM structure of Nav1.7 with LTG -

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Basic information

Entry
Database: PDB / ID: 8thh
TitleCryo-EM structure of Nav1.7 with LTG
Components
  • (Sodium channel subunit beta- ...) x 2
  • Sodium channel protein type 9 subunit alpha
KeywordsMEMBRANE PROTEIN / Cryo-EM / sodium channel / VGSC / Nav1.7
Function / homology
Function and homology information


response to pyrethroid / corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / action potential propagation / detection of mechanical stimulus involved in sensory perception / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / regulation of atrial cardiac muscle cell membrane depolarization / membrane depolarization during Purkinje myocyte cell action potential / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / cardiac conduction ...response to pyrethroid / corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / action potential propagation / detection of mechanical stimulus involved in sensory perception / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / regulation of atrial cardiac muscle cell membrane depolarization / membrane depolarization during Purkinje myocyte cell action potential / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / cardiac conduction / membrane depolarization during cardiac muscle cell action potential / membrane depolarization during action potential / positive regulation of sodium ion transport / regulation of sodium ion transmembrane transport / axon initial segment / regulation of ventricular cardiac muscle cell membrane repolarization / cardiac muscle cell action potential involved in contraction / node of Ranvier / voltage-gated sodium channel complex / sodium channel inhibitor activity / locomotion / neuronal action potential propagation / Interaction between L1 and Ankyrins / voltage-gated sodium channel activity / detection of temperature stimulus involved in sensory perception of pain / Phase 0 - rapid depolarisation / behavioral response to pain / regulation of heart rate by cardiac conduction / intercalated disc / sodium channel regulator activity / membrane depolarization / neuronal action potential / cardiac muscle contraction / axon terminus / sensory perception of pain / T-tubule / sodium ion transmembrane transport / axon guidance / post-embryonic development / circadian rhythm / positive regulation of neuron projection development / response to toxic substance / Sensory perception of sweet, bitter, and umami (glutamate) taste / nervous system development / response to heat / perikaryon / chemical synaptic transmission / gene expression / transmembrane transporter binding / cell adhesion / inflammatory response / axon / synapse / extracellular region / plasma membrane
Similarity search - Function
Sodium channel subunit beta-1/beta-3 / Myelin P0 protein-related / Voltage-gated Na+ ion channel, cytoplasmic domain / Cytoplasmic domain of voltage-gated Na+ ion channel / Sodium ion transport-associated / Voltage-gated sodium channel alpha subunit, inactivation gate / Sodium ion transport-associated / SCN5A-like, C-terminal IQ motif / Voltage gated sodium channel, alpha subunit / Voltage-gated cation channel calcium and sodium ...Sodium channel subunit beta-1/beta-3 / Myelin P0 protein-related / Voltage-gated Na+ ion channel, cytoplasmic domain / Cytoplasmic domain of voltage-gated Na+ ion channel / Sodium ion transport-associated / Voltage-gated sodium channel alpha subunit, inactivation gate / Sodium ion transport-associated / SCN5A-like, C-terminal IQ motif / Voltage gated sodium channel, alpha subunit / Voltage-gated cation channel calcium and sodium / Short calmodulin-binding motif containing conserved Ile and Gln residues. / IQ motif, EF-hand binding site / Voltage-dependent channel domain superfamily / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Ion transport domain / Ion transport protein / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Chem-IYJ / 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE / Chem-P5S / 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / CHOLESTEROL HEMISUCCINATE / Sodium channel regulatory subunit beta-2 / Sodium channel regulatory subunit beta-1 / Sodium channel protein type 9 subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsFan, X. / Huang, J. / Yan, N.
Funding support France, 1items
OrganizationGrant numberCountry
Human Frontier Science Program (HFSP) France
CitationJournal: 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
DepositionJul 16, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 22, 2023Provider: repository / Type: Initial release
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Revision 1.1Nov 20, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2May 21, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1May 21, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Sodium channel protein type 9 subunit alpha
B: Sodium channel subunit beta-1
C: Sodium channel subunit beta-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)286,76427
Polymers275,7083
Non-polymers11,05624
Water18010
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Sodium channel protein type 9 subunit alpha / Neuroendocrine sodium channel / hNE-Na / Peripheral sodium channel 1 / PN1 / Sodium channel protein ...Neuroendocrine sodium channel / hNE-Na / Peripheral sodium channel 1 / PN1 / Sodium channel protein type IX subunit alpha / Voltage-gated sodium channel subunit alpha Nav1.7


Mass: 226620.047 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SCN9A, NENA / Production host: Homo sapiens (human) / References: UniProt: Q15858

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Sodium channel subunit beta- ... , 2 types, 2 molecules BC

#2: Protein Sodium channel subunit beta-1


Mass: 24732.115 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SCN1B / Production host: Homo sapiens (human) / References: UniProt: Q07699
#3: Protein Sodium channel subunit beta-2


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

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Sugars , 2 types, 8 molecules

#4: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#5: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 6 types, 26 molecules

#6: Chemical ChemComp-IYJ / (6M)-6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine


Mass: 256.091 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H7Cl2N5 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C31H50O4
#8: Chemical
ChemComp-LPE / 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE / LPC-ETHER


Mass: 510.708 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C26H57NO6P
#9: Chemical ChemComp-PCW / 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / (Z,Z)-4-HYDROXY-N,N,N-TRIMETHYL-10-OXO-7-[(1-OXO-9-OCTADECENYL)OXY]-3,5,9-TRIOXA-4-PHOSPHAHEPTACOS-18-EN-1-AMINIUM-4-OXIDE


Mass: 787.121 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C44H85NO8P / Comment: DOPC, phospholipid*YM
#10: Chemical ChemComp-P5S / O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine / phosphatidyl serine


Mass: 792.075 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C42H82NO10P
#11: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 10 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human voltage-gated sodium channel Nav1.7 with beta subunits
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1400 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 40 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 294629 / Algorithm: BACK PROJECTION / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00513812
ELECTRON MICROSCOPYf_angle_d0.81118656
ELECTRON MICROSCOPYf_dihedral_angle_d9.062316
ELECTRON MICROSCOPYf_chiral_restr0.042134
ELECTRON MICROSCOPYf_plane_restr0.0042208

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