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- PDB-7k18: Cardiac Sodium channel with toxin bound -

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Basic information

Entry
Database: PDB / ID: 7k18
TitleCardiac Sodium channel with toxin bound
Components
  • Alpha-like toxin Lqh3
  • Sodium channel protein type 5 subunit alpha, Enhanced Green fluorescent protein
KeywordsMEMBRANE PROTEIN / Ion channel / Toxin bound
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 / sodium channel complex / AV node cell action potential / 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 / sodium channel complex / AV node cell action potential / 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 / membrane depolarization during AV node cell action potential / regulation of sodium ion transmembrane transport / membrane depolarization during bundle of His cell action potential / brainstem development / membrane depolarization during Purkinje myocyte cell action potential / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / positive regulation of action potential / atrial cardiac muscle 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 / sodium ion import across plasma membrane / positive regulation of sodium ion transport / 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 / regulation of heart rate by cardiac conduction / odontogenesis of dentin-containing tooth / 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
Chem-6OU / Sodium channel protein type 5 subunit alpha / Green fluorescent protein / Alpha-like toxin Lqh3
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Aequorea victoria (jellyfish)
Leiurus hebraeus (scorpion)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsJiang, D. / Catterall, W.A.
Funding support United States, 2items
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, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 20, 2021Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
A: Sodium channel protein type 5 subunit alpha, Enhanced Green fluorescent protein
B: Alpha-like toxin Lqh3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)225,65817
Polymers216,1042
Non-polymers9,55515
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Sodium channel protein type 5 subunit alpha, Enhanced Green fluorescent protein / / Sodium channel protein cardiac muscle subunit alpha / Sodium channel protein type V subunit alpha / ...Sodium channel protein cardiac muscle subunit alpha / Sodium channel protein type V subunit alpha / Voltage-gated sodium channel subunit alpha Nav1.5


Mass: 209037.781 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Loops truncated sodium channel with EGFP and FLAG tag fused at the C-terminus
Source: (gene. exp.) Rattus norvegicus (Norway rat), (gene. exp.) Aequorea victoria (jellyfish)
Gene: Scn5a, GFP / Cell line (production host): HEK293S / Production host: Homo sapiens (human) / References: UniProt: P15389, UniProt: P42212
#2: Protein Alpha-like toxin Lqh3 / Lqh III / LqhIII


Mass: 7065.984 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Leiurus hebraeus (scorpion) / References: UniProt: P56678

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Sugars , 3 types, 4 molecules

#3: 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: 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
#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: 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 / 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 , 1 types, 11 molecules

#6: 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.: 11 / Source method: obtained synthetically / Formula: C39H76NO8P / Comment: phospholipid*YM

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Details

Has ligand of interestN

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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
1Cryo-EM map for sodium channel and scorpion toxin complexCOMPLEX#1-#20MULTIPLE SOURCES
2Sodium channel protein type 5 subunit alphaCOMPLEX#11RECOMBINANT
3Alpha-like toxin Lqh3COMPLEX#21NATURAL
Molecular weightValue: 0.25 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Rattus norvegicus (Norway rat)10116
23Leiurus hebraeus (scorpion)6884
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 6
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaClSodium chloride1
20.006 %glyco-diosgeninGDN1011
325 mMImidazole1
SpecimenConc.: 4.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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 / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.17.1_3660: / Classification: refinement
EM software
IDNameCategory
2Leginonimage acquisition
4GctfCTF correction
9RELIONinitial Euler assignment
10RELIONfinal Euler assignment
11RELIONclassification
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 267595 / Symmetry type: POINT
Atomic model buildingB value: 59 / Protocol: RIGID BODY FIT / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00410216
ELECTRON MICROSCOPYf_angle_d0.71613857
ELECTRON MICROSCOPYf_dihedral_angle_d19.6841546
ELECTRON MICROSCOPYf_chiral_restr0.0411624
ELECTRON MICROSCOPYf_plane_restr0.0051637

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