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- EMDB-20949: Cardiac sodium channel with flecainide -

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Basic information

Entry
Database: EMDB / ID: EMD-20949
TitleCardiac sodium channel with flecainide
Map dataCryoEM map for a drug binding structure
Sample
  • Complex: cardiac sodium channel complex with flecainide
    • Protein or peptide: Sodium channel protein type 5 subunit alpha,Green fluorescent protein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en
  • Ligand: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate
  • Ligand: Flecainide
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 / 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 / response to organic cyclic compound / Z disc / 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 / membrane / plasma membrane
Similarity search - Function
Voltage gated sodium channel, alpha-5 subunit / 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 / Voltage-dependent channel domain superfamily / Green fluorescent protein, GFP ...Voltage gated sodium channel, alpha-5 subunit / 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 / 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
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat) / Aequorea victoria (jellyfish)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.24 Å
AuthorsJiang D / Shi H / Tonggu L / Lenaeus MJ / Zheng N / Catterall WA
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01 HL112808 United States
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Cell / Year: 2020
Title: Structure of the Cardiac Sodium Channel.
Authors: Daohua Jiang / Hui Shi / Lige Tonggu / Tamer M Gamal El-Din / Michael J Lenaeus / Yan Zhao / Craig Yoshioka / Ning Zheng / William A Catterall /
Abstract: Voltage-gated sodium channel Na1.5 generates cardiac action potentials and initiates the heartbeat. Here, we report structures of Na1.5 at 3.2-3.5 Å resolution. Na1.5 is distinguished from other ...Voltage-gated sodium channel Na1.5 generates cardiac action potentials and initiates the heartbeat. Here, we report structures of Na1.5 at 3.2-3.5 Å resolution. Na1.5 is distinguished from other sodium channels by a unique glycosyl moiety and loss of disulfide-bonding capability at the Naβ subunit-interaction sites. The antiarrhythmic drug flecainide specifically targets the central cavity of the pore. The voltage sensors are partially activated, and the fast-inactivation gate is partially closed. Activation of the voltage sensor of Domain III allows binding of the isoleucine-phenylalanine-methionine (IFM) motif to the inactivation-gate receptor. Asp and Ala, in the selectivity motif DEKA, line the walls of the ion-selectivity filter, whereas Glu and Lys are in positions to accept and release Na ions via a charge-delocalization network. Arrhythmia mutation sites undergo large translocations during gating, providing a potential mechanism for pathogenic effects. Our results provide detailed insights into Na1.5 structure, pharmacology, activation, inactivation, ion selectivity, and arrhythmias.
History
DepositionNov 14, 2019-
Header (metadata) releaseDec 4, 2019-
Map releaseJan 1, 2020-
UpdateJul 29, 2020-
Current statusJul 29, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 5
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 5
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6uz0
  • Surface level: 5
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_20949.png

Downloads & links

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Map

FileDownload / File: emd_20949.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryoEM map for a drug binding structure
Voxel sizeX=Y=Z: 1.056 Å
Density
Contour LevelBy AUTHOR: 5 / Movie #1: 5
Minimum - Maximum-29.431952 - 42.962135
Average (Standard dev.)-0.00997886 (±1.8050244)
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/NZ000
NX/NY/NZ720720720
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-29.43242.962-0.010

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Supplemental data

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Sample components

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Entire : cardiac sodium channel complex with flecainide

EntireName: cardiac sodium channel complex with flecainide
Components
  • Complex: cardiac sodium channel complex with flecainide
    • Protein or peptide: Sodium channel protein type 5 subunit alpha,Green fluorescent protein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en
  • Ligand: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate
  • Ligand: Flecainide

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Supramolecule #1: cardiac sodium channel complex with flecainide

SupramoleculeName: cardiac sodium channel complex with flecainide / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Rattus norvegicus (Norway rat) / Organ: heart
Recombinant expressionOrganism: Mammalian 1 orthobornavirus / Recombinant strain: HEK293 / Recombinant plasmid: pEG_BacMam
Molecular weightTheoretical: 250 KDa

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Macromolecule #1: Sodium channel protein type 5 subunit alpha,Green fluorescent protein

MacromoleculeName: Sodium channel protein type 5 subunit alpha,Green fluorescent protein
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Aequorea victoria (jellyfish) / Organ: HEART
Molecular weightTheoretical: 209.037781 KDa
Recombinant expressionOrganism: Mammalian 1 orthobornavirus
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 #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 2 / 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 #5: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]sp...

MacromoleculeName: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en
type: ligand / ID: 5 / Number of copies: 5 / Formula: 9Z9
Molecular weightTheoretical: 544.805 Da
Chemical component information

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

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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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Macromolecule #7: Flecainide

MacromoleculeName: Flecainide / type: ligand / ID: 7 / Number of copies: 1 / Formula: K4D
Molecular weightTheoretical: 414.343 Da
Chemical component information

ChemComp-K4D:
Flecainide / medication*YM / Flecainide

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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

Concentration5.0 mg/mL
BufferpH: 6
Component:
ConcentrationFormulaName
150.0 mMNaClSodium chloridesodium chloride
25.0 mMImidezoleImidazole
GridModel: UltrAuFoil / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 0.133 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
Details: waiting for 20s, blot for 2.5-3.5s before plunging.
DetailsThis sample include channel protein solubilized with GDN detergent.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Calibrated defocus max: 3.0 µm / Calibrated defocus min: 0.8 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.8 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 130000
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
TemperatureMin: 90.0 K / Max: 103.0 K
DetailsSquares on grids were manually screened before data collection
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Dimensions - Width: 3838 pixel / Digitization - Dimensions - Height: 3710 pixel / Digitization - Frames/image: 1-40 / Number grids imaged: 2 / Number real images: 5000 / Average exposure time: 8.0 sec. / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 2369854 / Details: particles were autopicked in relion3
CTF correctionSoftware - Name: Gctf
Startup modelType of model: OTHER
Details: A 40-angstrom low-pass filtered NavPas EM-map was used as initial model.
Initial angle assignmentType: RANDOM ASSIGNMENT / Software - Name: RELION
Final 3D classificationNumber classes: 4 / Avg.num./class: 200000 / Software - Name: RELION
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.24 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cisTEM / Number images used: 513604
DetailsThe images were manually inspected.
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6agf


Chain - Chain ID: A
RefinementSpace: REAL / Protocol: RIGID BODY FIT / Overall B value: 60
Output model

PDB-6uz0:
Cardiac sodium channel with flecainide

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