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- PDB-7w77: cryo-EM structure of human NaV1.3/beta1/beta2-bulleyaconitineA -

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Basic information

Entry
Database: PDB / ID: 7w77
Titlecryo-EM structure of human NaV1.3/beta1/beta2-bulleyaconitineA
Components
  • (Sodium channel subunit beta- ...) x 2
  • Sodium channel protein type 3 subunit alpha
KeywordsMEMBRANE PROTEIN / Ion channel / Drug / Antagonist
Function / homology
Function and homology information


corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / response to pyrethroid / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / membrane depolarization during Purkinje myocyte cell action potential / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / regulation of atrial cardiac muscle cell membrane depolarization / cardiac conduction / regulation of sodium ion transmembrane transport / membrane depolarization during cardiac muscle cell action potential ...corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / response to pyrethroid / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / membrane depolarization during Purkinje myocyte cell action potential / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / regulation of atrial cardiac muscle cell membrane depolarization / cardiac conduction / regulation of sodium ion transmembrane transport / membrane depolarization during cardiac muscle cell action potential / positive regulation of sodium ion transport / node of Ranvier / sodium channel inhibitor activity / membrane depolarization during action potential / voltage-gated sodium channel complex / cardiac muscle cell action potential involved in contraction / locomotion / regulation of ventricular cardiac muscle cell membrane repolarization / 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 / intercalated disc / sarcoplasm / sodium channel regulator activity / sodium ion transmembrane transport / cardiac muscle contraction / T-tubule / axon guidance / positive regulation of neuron projection development / Sensory perception of sweet, bitter, and umami (glutamate) taste / nervous system development / gene expression / response to heat / chemical synaptic transmission / perikaryon / transmembrane transporter binding / cell adhesion / 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 / Voltage gated sodium channel, alpha subunit / Voltage-gated cation channel calcium and sodium / IQ motif profile. ...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 / Voltage gated sodium channel, alpha subunit / Voltage-gated cation channel calcium and sodium / IQ motif profile. / 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-6OU / Chem-966 / Sodium channel regulatory subunit beta-2 / Sodium channel regulatory subunit beta-1 / Sodium channel protein type 3 subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsJiang, D. / Li, X.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2022
Title: Structural basis for modulation of human Na1.3 by clinical drug and selective antagonist.
Authors: Xiaojing Li / Feng Xu / Hao Xu / Shuli Zhang / Yiwei Gao / Hongwei Zhang / Yanli Dong / Yanchun Zheng / Bei Yang / Jianyuan Sun / Xuejun Cai Zhang / Yan Zhao / Daohua Jiang /
Abstract: Voltage-gated sodium (Na) channels play fundamental roles in initiating and propagating action potentials. Na1.3 is involved in numerous physiological processes including neuronal development, ...Voltage-gated sodium (Na) channels play fundamental roles in initiating and propagating action potentials. Na1.3 is involved in numerous physiological processes including neuronal development, hormone secretion and pain perception. Here we report structures of human Na1.3/β1/β2 in complex with clinically-used drug bulleyaconitine A and selective antagonist ICA121431. Bulleyaconitine A is located around domain I-II fenestration, providing the detailed view of the site-2 neurotoxin binding site. It partially blocks ion path and expands the pore-lining helices, elucidating how the bulleyaconitine A reduces peak amplitude but improves channel open probability. In contrast, ICA121431 preferentially binds to activated domain IV voltage-sensor, consequently strengthens the Ile-Phe-Met motif binding to its receptor site, stabilizes the channel in inactivated state, revealing an allosterically inhibitory mechanism of Na channels. Our results provide structural details of distinct small-molecular modulators binding sites, elucidate molecular mechanisms of their action on Na channels and pave a way for subtype-selective therapeutic development.
History
DepositionDec 3, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 6, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Sodium channel subunit beta-1
C: Sodium channel subunit beta-2
D: Sodium channel protein type 3 subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)285,99230
Polymers270,1253
Non-polymers15,86727
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area7310 Å2
ΔGint-1 kcal/mol
Surface area71640 Å2

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Components

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

#1: 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 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q07699
#2: Protein Sodium channel subunit beta-2 / Nav1.7 beta2 subunit


Mass: 24355.859 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SCN2B / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: O60939

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Protein , 1 types, 1 molecules D

#3: Protein Sodium channel protein type 3 subunit alpha / Sodium channel protein brain III subunit alpha / Sodium channel protein type III subunit alpha / ...Sodium channel protein brain III subunit alpha / Sodium channel protein type III subunit alpha / Voltage-gated sodium channel subtype III / Voltage-gated sodium channel subunit alpha Nav1.3


Mass: 221036.625 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SCN3A / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q9NY46

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Sugars , 3 types, 7 molecules

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


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#5: 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.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#6: 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: obtained synthetically / 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 , 3 types, 20 molecules

#7: Chemical ChemComp-9Z9 / (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en


Mass: 544.805 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C34H56O5 / Comment: detergent*YM
#8: Chemical
ChemComp-6OU / [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate


Mass: 717.996 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: C39H76NO8P / Comment: phospholipid*YM
#9: Chemical ChemComp-966 / [(1S,2R,3R,4R,5R,6S,8R,9S,13S,16S,17R,18R)-11-ethyl-5-hydroxy-6,16,18-trimethoxy-4-(4-methoxybenzoyl)-13-(methoxymethyl)-11-azahexacyclo[7.7.2.12,5.01,10.03,8.013,17]nonadecan-8-yl] acetate / Bulleyaconitine A


Mass: 627.765 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H49NO9 / Feature type: SUBJECT OF INVESTIGATION

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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: Sodium channel complex of type 3 subunit alpha with auxiliary subunits bata-1 and bata-2
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293
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
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19_4092: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1403849 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00312328
ELECTRON MICROSCOPYf_angle_d0.68216667
ELECTRON MICROSCOPYf_dihedral_angle_d9.2111811
ELECTRON MICROSCOPYf_chiral_restr0.0431930
ELECTRON MICROSCOPYf_plane_restr0.0051991

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