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- PDB-6j8e: Human Nav1.2-beta2-KIIIA ternary complex -

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Basic information

Entry
Database: PDB / ID: 6j8e
TitleHuman Nav1.2-beta2-KIIIA ternary complex
Components
  • (Sodium channel ...) x 2
  • Mu-conotoxin KIIIA
KeywordsMEMBRANE PROTEIN/TOXIN / transmembrane protein / MEMBRANE PROTEIN / MEMBRANE PROTEIN-TOXIN complex
Function / homology
Function and homology information


response to pyrethroid / 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 / intrinsic apoptotic signaling pathway in response to osmotic stress / nerve development / regulation of atrial cardiac muscle cell membrane depolarization / paranode region of axon / voltage-gated sodium channel complex / membrane depolarization during cardiac muscle cell action potential ...response to pyrethroid / 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 / intrinsic apoptotic signaling pathway in response to osmotic stress / nerve development / regulation of atrial cardiac muscle cell membrane depolarization / paranode region of axon / voltage-gated sodium channel complex / membrane depolarization during cardiac muscle cell action potential / dentate gyrus development / cardiac muscle cell action potential involved in contraction / node of Ranvier / high voltage-gated calcium channel activity / voltage-gated sodium channel activity / Interaction between L1 and Ankyrins / sodium ion transport / voltage-gated calcium channel complex / regulation of heart rate by cardiac conduction / Phase 0 - rapid depolarisation / calcium ion import across plasma membrane / neuronal action potential / sodium ion transmembrane transport / sodium channel regulator activity / intercalated disc / cardiac muscle contraction / T-tubule / myelination / determination of adult lifespan / Sensory perception of sweet, bitter, and umami (glutamate) taste / memory / presynaptic membrane / gene expression / nervous system development / response to heat / toxin activity / cellular response to hypoxia / chemical synaptic transmission / neuron apoptotic process / calmodulin binding / axon / glutamatergic synapse / synapse / extracellular region / membrane / plasma membrane
Similarity search - Function
Myelin P0 protein-related / Voltage-gated Na+ ion channel, cytoplasmic domain / Cytoplasmic domain of voltage-gated Na+ ion channel / Voltage-gated sodium channel alpha subunit, inactivation gate / Sodium ion transport-associated / Sodium ion transport-associated / 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 profile. ...Myelin P0 protein-related / Voltage-gated Na+ ion channel, cytoplasmic domain / Cytoplasmic domain of voltage-gated Na+ ion channel / Voltage-gated sodium channel alpha subunit, inactivation gate / Sodium ion transport-associated / Sodium ion transport-associated / 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 profile. / 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 / Immunoglobulins / Immunoglobulin-like fold / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Sodium channel subunit beta-2 / Mu-conotoxin KIIIB / Sodium channel protein type 2 subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
Conus kinoshitai (invertebrata)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsPan, X. / Li, Z. / Huang, X. / Huang, G. / Yan, N.
Funding support China, 8items
OrganizationGrant numberCountry
Ministry of Science and Technology (China)2016YFA0500402 China
Ministry of Science and Technology (China)2017YFA0505200 China
Ministry of Science and Technology (China)2015CB910101 China
National Natural Science Foundation of China31621092 China
National Natural Science Foundation of China31630017 China
National Natural Science Foundation of China81861138009 China
National Natural Science Foundation of China91753205 China
National Natural Science Foundation of China31800628 China
CitationJournal: Science / Year: 2019
Title: Molecular basis for pore blockade of human Na channel Na1.2 by the μ-conotoxin KIIIA.
Authors: Xiaojing Pan / Zhangqiang Li / Xiaoshuang Huang / Gaoxingyu Huang / Shuai Gao / Huaizong Shen / Lei Liu / Jianlin Lei / Nieng Yan /
Abstract: The voltage-gated sodium channel Na1.2 is responsible for the initiation and propagation of action potentials in the central nervous system. We report the cryo-electron microscopy structure of human ...The voltage-gated sodium channel Na1.2 is responsible for the initiation and propagation of action potentials in the central nervous system. We report the cryo-electron microscopy structure of human Na1.2 bound to a peptidic pore blocker, the μ-conotoxin KIIIA, in the presence of an auxiliary subunit, β2, to an overall resolution of 3.0 angstroms. The immunoglobulin domain of β2 interacts with the shoulder of the pore domain through a disulfide bond. The 16-residue KIIIA interacts with the extracellular segments in repeats I to III, placing Lys at the entrance to the selectivity filter. Many interacting residues are specific to Na1.2, revealing a molecular basis for KIIIA specificity. The structure establishes a framework for the rational design of subtype-specific blockers for Na channels.
History
DepositionJan 18, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 27, 2019Provider: repository / Type: Initial release
Revision 1.1Apr 10, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 6, 2019Group: Data collection / Other / Category: cell / Item: _cell.Z_PDB
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / em_entity_assembly / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_struct_conn_angle / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.Cartn_x / _atom_site.Cartn_y ..._atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_entity_id / _chem_comp.name / _chem_comp.type / _em_entity_assembly.entity_id_list / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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Structure visualization

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Assembly

Deposited unit
C: Sodium channel subunit beta-2
A: Sodium channel protein type 2 subunit alpha
D: Mu-conotoxin KIIIA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)251,1879
Polymers248,9633
Non-polymers2,2246
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy, SDS-PAGE and Mass-spectrometry idenitified the presence of Nav1.2 alpha subunit and the beta2 subunit. The presence of KIIIA was confirmed by electron density analysis.
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area4760 Å2
ΔGint1 kcal/mol
Surface area67280 Å2

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Components

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Sodium channel ... , 2 types, 2 molecules CA

#1: Protein Sodium channel subunit beta-2 /


Mass: 14267.261 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
#2: Protein Sodium channel protein type 2 subunit alpha / / HBSC II / Sodium channel protein brain II subunit alpha / Sodium channel protein type II subunit ...HBSC II / Sodium channel protein brain II subunit alpha / Sodium channel protein type II subunit alpha / Voltage-gated sodium channel subunit alpha Nav1.2


Mass: 232800.172 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SCN2A, NAC2, SCN2A1, SCN2A2 / Production host: Homo sapiens (human) / References: UniProt: Q99250

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Protein/peptide , 1 types, 1 molecules D

#3: Protein/peptide Mu-conotoxin KIIIA


Mass: 1895.220 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Conus kinoshitai (invertebrata) / References: UniProt: P0C195

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Sugars , 3 types, 4 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: obtained synthetically
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam 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
[]{[(4+1)][b-D-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.: 2 / Source method: obtained synthetically
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
#6: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / 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 , 2 types, 2 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.: 1 / Source method: obtained synthetically / Formula: C34H56O5 / Comment: detergent*YM
#8: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na

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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

Component
IDNameTypeEntity IDParent-IDSource
1Ternary complex of Nav1.2-beta2-KIIIACOMPLEX#1-#30RECOMBINANT
2Nav1.2-beta2COMPLEX#1-#21RECOMBINANT
3KIIIACOMPLEX1RECOMBINANT
Molecular weightValue: 252 kDa/nm / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Conus kinoshitai (invertebrata)376876
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 5.9
SpecimenConc.: 1 mg/ml / Embedding 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 FIELDBright-field microscopy
Image recordingElectron dose: 48 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 200275 / Symmetry type: POINT

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