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- EMDB-22621: Cardiac Sodium channel with toxin bound -

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Basic information

Entry
Database: EMDB / ID: EMD-22621
TitleCardiac Sodium channel with toxin bound
Map datacryo-EM map of sodium channel with toxin
Sample
  • Complex: Cryo-EM map for sodium channel and scorpion toxin complex
    • Complex: Sodium channel protein type 5 subunit alpha
      • Protein or peptide: Sodium channel protein type 5 subunit alpha, Enhanced Green fluorescent protein
    • Complex: Alpha-like toxin Lqh3
      • Protein or peptide: Alpha-like toxin Lqh3
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate
Function / homology
Function and homology information


voltage-gated sodium channel activity involved in AV node cell action potential / voltage-gated sodium channel activity involved in bundle of His cell action potential / voltage-gated sodium channel activity involved in SA node cell action potential / bundle of His cell action potential / AV node cell action potential / sodium channel complex / SA node cell action potential / AV node cell to bundle of His cell communication / membrane depolarization during SA node cell action potential / cardiac ventricle development ...voltage-gated sodium channel activity involved in AV node cell action potential / voltage-gated sodium channel activity involved in bundle of His cell action potential / voltage-gated sodium channel activity involved in SA node cell action potential / bundle of His cell action potential / AV node cell action potential / sodium channel complex / SA node cell action potential / AV node cell to bundle of His cell communication / membrane depolarization during SA node cell action potential / cardiac ventricle development / response to denervation involved in regulation of muscle adaptation / regulation of ventricular cardiac muscle cell membrane depolarization / regulation of atrial cardiac muscle cell membrane repolarization / membrane depolarization during atrial cardiac muscle cell action potential / membrane depolarization during action potential / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / regulation of sodium ion transmembrane transport / brainstem development / membrane depolarization during AV node cell action potential / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / membrane depolarization during bundle of His cell action potential / positive regulation of action potential / atrial cardiac muscle cell action potential / membrane depolarization during Purkinje myocyte cell action potential / telencephalon development / regulation of atrial cardiac muscle cell membrane depolarization / voltage-gated sodium channel complex / membrane depolarization during cardiac muscle cell action potential / positive regulation of sodium ion transport / sodium ion import across plasma membrane / cardiac muscle cell action potential involved in contraction / ventricular cardiac muscle cell action potential / regulation of cardiac muscle cell contraction / voltage-gated sodium channel activity / regulation of ventricular cardiac muscle cell membrane repolarization / sodium channel inhibitor activity / ankyrin binding / positive regulation of heart rate / sodium ion transport / fibroblast growth factor binding / nitric-oxide synthase binding / odontogenesis of dentin-containing tooth / regulation of heart rate by cardiac conduction / membrane depolarization / neuronal action potential / sodium ion transmembrane transport / intercalated disc / lateral plasma membrane / cardiac muscle contraction / T-tubule / cellular response to calcium ion / regulation of heart rate / cerebellum development / bioluminescence / generation of precursor metabolites and energy / positive regulation of epithelial cell proliferation / caveola / sarcolemma / defense response / response to organic cyclic compound / Z disc / toxin activity / scaffold protein binding / transmembrane transporter binding / calmodulin binding / axon / protein domain specific binding / ubiquitin protein ligase binding / protein kinase binding / perinuclear region of cytoplasm / enzyme binding / cell surface / endoplasmic reticulum / extracellular region / membrane / plasma membrane
Similarity search - Function
Voltage gated sodium channel, alpha-5 subunit / LCN-type cysteine-stabilized alpha/beta (CS-alpha/beta) domain / Scorpion long chain toxin / LCN-type cysteine-stabilized alpha/beta (CS-alpha/beta) domain profile. / Scorpion long chain toxin/defensin / Scorpion toxin-like domain / Knottins / Knottin, scorpion toxin-like / Voltage-gated Na+ ion channel, cytoplasmic domain / Cytoplasmic domain of voltage-gated Na+ ion channel ...Voltage gated sodium channel, alpha-5 subunit / LCN-type cysteine-stabilized alpha/beta (CS-alpha/beta) domain / Scorpion long chain toxin / LCN-type cysteine-stabilized alpha/beta (CS-alpha/beta) domain profile. / Scorpion long chain toxin/defensin / Scorpion toxin-like domain / Knottins / Knottin, scorpion toxin-like / 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 / Knottin, scorpion toxin-like superfamily / Voltage-gated cation channel calcium and sodium / Voltage-dependent channel domain superfamily / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Sodium channel protein type 5 subunit alpha / Green fluorescent protein / Alpha-like toxin Lqh3
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat) / Leiurus hebraeus (scorpion) / Aequorea victoria (jellyfish) / Deathstalker scorpion (scorpion)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsJiang D / Catterall WA
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL112808 United States
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Nat Commun / Year: 2021
Title: Structural basis for voltage-sensor trapping of the cardiac sodium channel by a deathstalker scorpion toxin.
Authors: Daohua Jiang / Lige Tonggu / Tamer M Gamal El-Din / Richard Banh / Régis Pomès / Ning Zheng / William A Catterall /
Abstract: Voltage-gated sodium (Na) channels initiate action potentials in excitable cells, and their function is altered by potent gating-modifier toxins. The α-toxin LqhIII from the deathstalker scorpion ...Voltage-gated sodium (Na) channels initiate action potentials in excitable cells, and their function is altered by potent gating-modifier toxins. The α-toxin LqhIII from the deathstalker scorpion inhibits fast inactivation of cardiac Na1.5 channels with IC = 11.4 nM. Here we reveal the structure of LqhIII bound to Na1.5 at 3.3 Å resolution by cryo-EM. LqhIII anchors on top of voltage-sensing domain IV, wedged between the S1-S2 and S3-S4 linkers, which traps the gating charges of the S4 segment in a unique intermediate-activated state stabilized by four ion-pairs. This conformational change is propagated inward to weaken binding of the fast inactivation gate and favor opening the activation gate. However, these changes do not permit Na permeation, revealing why LqhIII slows inactivation of Na channels but does not open them. Our results provide important insights into the structural basis for gating-modifier toxin binding, voltage-sensor trapping, and fast inactivation of Na channels.
History
DepositionSep 7, 2020-
Header (metadata) releaseJan 20, 2021-
Map releaseJan 20, 2021-
UpdateJan 20, 2021-
Current statusJan 20, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.018
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.018
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7k18
  • Surface level: 0.018
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_22621.png

Downloads & links

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Map

FileDownload / File: emd_22621.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcryo-EM map of sodium channel with toxin
Voxel sizeX=Y=Z: 1.056 Å
Density
Contour LevelBy AUTHOR: 0.015 / Movie #1: 0.018
Minimum - Maximum-0.08389278 - 0.14828731
Average (Standard dev.)-3.622136e-05 (±0.003499711)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 270.336 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0561.0561.056
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z270.336270.336270.336
α/β/γ90.00090.00090.000
start NX/NY/NZ107101134
NX/NY/NZ14113986
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.0840.148-0.000

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Supplemental data

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Sample components

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Entire : Cryo-EM map for sodium channel and scorpion toxin complex

EntireName: Cryo-EM map for sodium channel and scorpion toxin complex
Components
  • Complex: Cryo-EM map for sodium channel and scorpion toxin complex
    • Complex: Sodium channel protein type 5 subunit alpha
      • Protein or peptide: Sodium channel protein type 5 subunit alpha, Enhanced Green fluorescent protein
    • Complex: Alpha-like toxin Lqh3
      • Protein or peptide: Alpha-like toxin Lqh3
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate

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Supramolecule #1: Cryo-EM map for sodium channel and scorpion toxin complex

SupramoleculeName: Cryo-EM map for sodium channel and scorpion toxin complex
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Molecular weightTheoretical: 250 KDa

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Supramolecule #2: Sodium channel protein type 5 subunit alpha

SupramoleculeName: Sodium channel protein type 5 subunit alpha / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Rattus norvegicus (Norway rat)
Recombinant expressionOrganism: Homo sapiens (human)

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Supramolecule #3: Alpha-like toxin Lqh3

SupramoleculeName: Alpha-like toxin Lqh3 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Leiurus hebraeus (scorpion)

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Macromolecule #1: Sodium channel protein type 5 subunit alpha, Enhanced Green fluor...

MacromoleculeName: Sodium channel protein type 5 subunit alpha, Enhanced Green fluorescent protein
type: protein_or_peptide / ID: 1
Details: Loops truncated sodium channel with EGFP and FLAG tag fused at the C-terminus
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Aequorea victoria (jellyfish)
Molecular weightTheoretical: 209.037781 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MANLLLPRGT SSFRRFTRES LAAIEKRMAE KQARGGSATS QESREGLQEE EAPRPQLDLQ ASKKLPDLYG NPPRELIGEP LEDLDPFYS TQKTFIVLNK GKTIFRFSAT NALYVLSPFH PVRRAAVKIL VHSLFSMLIM CTILTNCVFM AQHDPPPWTK Y VEYTFTAI ...String:
MANLLLPRGT SSFRRFTRES LAAIEKRMAE KQARGGSATS QESREGLQEE EAPRPQLDLQ ASKKLPDLYG NPPRELIGEP LEDLDPFYS TQKTFIVLNK GKTIFRFSAT NALYVLSPFH PVRRAAVKIL VHSLFSMLIM CTILTNCVFM AQHDPPPWTK Y VEYTFTAI YTFESLVKIL ARGFCLHAFT FLRDPWNWLD FSVIVMAYTT EFVDLGNVSA LRTFRVLRAL KTISVISGLK TI VGALIQS VKKLADVMVL TVFCLSVFAL IGLQLFMGNL RHKCVRNFTE LNGTNGSVEA DGLVWNSLDV YLNDPANYLL KNG TTDVLL CGNSSDAGTC PEGYRCLKAG ENPDHGYTSF DSFAWAFLAL FRLMTQDCWE RLYQQTLRSA GKIYMIFFML VIFL GSFYL VNLILAVVAM AYEEQNQATI AETEEKEKRF QEAMEMLKKE HEALTIRGVD TVSRSSARQR ALSAVSVLTS ALEEL EESH RKCPPCWNRF AQHYLIWECC PLWMSIKQKV KFVVMDPFAD LTITMCIVLN TLFMALEHYN MTAEFEEMLQ VGNLVF TGI FTAEMTFKII ALDPYYYFQQ GWNIFDSIIV ILSLMELGLS RMGNLSVLRS FRLLRVFKLA KSWPTLNTLI KIIGNSV GA LGNLTLVLAI IVFIFAVVGM QLFGKNYSEL RHRISDSGLL PRWHMMDFFH AFLIIFRILC GEWIETMWDC MEVSGQSL C LLVFLLVMVI GNLVVLNLFL ALLLSSFSAD NLTAPDEDGE MNNLQLALAR IQRGLRFVKR TTWDFCCGIL RRRPKKPAA LATHSQLPSC ITAPRSPPPP EVEKVPPARK ETRFEEDKRP GQGTPGDSEP VCVPIAVAES DTEDQEEDEE NGKVWWRLRK TCYRIVEHS WFETFIIFMI LLSSGALAFE DIYLEERKTI KVLLEYADKM FTYVFVLEML LKWVAYGFKK YFTNAWCWLD F LIVDVSLV SLVANTLGFA EMGPIKSLRT LRALRPLRAL SRFEGMRVVV NALVGAIPSI MNVLLVCLIF WLIFSIMGVN LF AGKFGRC INQTEGDLPL NYTIVNNKSE CESFNVTGEL YWTKVKVNFD NVGAGYLALL QVATFKGWMD IMYAAVDSRG YEE QPQWED NLYMYIYFVV FIIFGSFFTL NLFIGVIIDN FNQQKKKLGG QDIFMTEEQK KYYNAMKKLG SKKPQKPIPR PLNK YQGFI FDIVTKQAFD VTIMFLICLN MVTMMVETDD QSPEKVNILA KINLLFVAIF TGECIVKMAA LRHYYFTNSW NIFDF VVVI LSIVGTVLSD IIQKYFFSPT LFRVIRLARI GRILRLIRGA KGIRTLLFAL MMSLPALFNI GLLLFLVMFI YSIFGM ANF AYVKWEAGID DMFNFQTFAN SMLCLFQITT SAGWDGLLSP ILNTGPPYCD PNLPNSNGSR GNCGSPAVGI LFFTTYI II SFLIVVNMYI AIILENFSVA TEESTEPLSE DDFDMFYEIW EKFDPEATQF IEYLALSDFA DALSEPLRIA KPNQISLI N MDLPMVSGDR IHCMDILFAF TKRVLGESGE MDALKIQMEE KFMAANPSKI SYEPITTTLE VLFQGPGSMV SKGEELFTG VVPILVELDG DVNGHKFSVS GEGEGDATYG KLTLKFICTT GKLPVPWPTL VTTLTYGVQC FSRYPDHMKQ HDFFKSAMPE GYVQERTIF FKDDGNYKTR AEVKFEGDTL VNRIELKGID FKEDGNILGH KLEYNYNSHN VYIMADKQKN GIKVNFKIRH N IEDGSVQL ADHYQQNTPI GDGPVLLPDN HYLSTQSALS KDPNEKRDHM VLLEFVTAAG ITLGMDELYK GSDYKDDDDK

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Macromolecule #2: Alpha-like toxin Lqh3

MacromoleculeName: Alpha-like toxin Lqh3 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Deathstalker scorpion (scorpion)
Molecular weightTheoretical: 7.065984 KDa
SequenceString:
VRDGYIAQPE NCVYHCFPGS SGCDTLCKEK GGTSGHCGFK VGHGLACWCN ALPDNVGIIV EGEKCHS

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 1 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Macromolecule #6: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyl...

MacromoleculeName: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate
type: ligand / ID: 6 / Number of copies: 11 / Formula: 6OU
Molecular weightTheoretical: 717.996 Da
Chemical component information

ChemComp-6OU:
[(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate / phospholipid*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration4.5 mg/mL
BufferpH: 6
Component:
ConcentrationFormulaName
150.0 mMNaClSodium chloridesodium chloride
0.006 %GDN101glyco-diosgenin
25.0 mMImidazole
GridModel: UltrAuFoil / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: Gctf
Initial angle assignmentType: RANDOM ASSIGNMENT / Software - Name: RELION
Final 3D classificationNumber classes: 3 / Software - Name: RELION
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 267595
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT / Overall B value: 59
Output model

PDB-7k18:
Cardiac Sodium channel with toxin bound

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