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- EMDB-60865: Nav1.5 in complex with TTX -

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Basic information

Entry
Database: EMDB / ID: EMD-60865
TitleNav1.5 in complex with TTX
Map dataCryo-EM map of Nav1.5 in complex with TTX
Sample
  • Complex: Nav1.5 in complex with TTX
    • Protein or peptide: Sodium channel protein type 5 subunit alpha
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (1R,5R,6R,7R,9S,11S,12S,13S,14S)-3-amino-14-(hydroxymethyl)-8,10-dioxa-2,4-diazatetracyclo[7.3.1.1~7,11~.0~1,6~]tetradec-3-ene-5,9,12,13,14-pentol (non-preferred name)
  • Ligand: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en
KeywordsVoltage-gated sodium channel / MEMBRANE PROTEIN
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 Purkinje myocyte action potential / voltage-gated sodium channel activity involved in SA node cell action potential / bundle of His cell action potential / regulation of ventricular cardiac muscle cell membrane depolarization / 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 ...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 Purkinje myocyte action potential / voltage-gated sodium channel activity involved in SA node cell action potential / bundle of His cell action potential / regulation of ventricular cardiac muscle cell membrane depolarization / 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 / response to denervation involved in regulation of muscle adaptation / membrane depolarization during atrial cardiac muscle cell action potential / cardiac ventricle development / regulation of atrial cardiac muscle cell membrane repolarization / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / brainstem development / membrane depolarization during AV node cell action potential / membrane depolarization during bundle of His cell action potential / membrane depolarization during Purkinje myocyte cell action potential / regulation of atrial cardiac muscle cell membrane depolarization / positive regulation of action potential / atrial cardiac muscle cell action potential / telencephalon development / cardiac conduction system development / membrane depolarization during cardiac muscle cell action potential / membrane depolarization during action potential / positive regulation of sodium ion transport / regulation of sodium ion transmembrane transport / ventricular cardiac muscle cell action potential / regulation of ventricular cardiac muscle cell membrane repolarization / cardiac muscle cell action potential involved in contraction / voltage-gated sodium channel complex / regulation of cardiac muscle cell contraction / Interaction between L1 and Ankyrins / ankyrin binding / voltage-gated sodium channel activity / sodium ion transport / nitric-oxide synthase binding / Phase 0 - rapid depolarisation / fibroblast growth factor binding / odontogenesis of dentin-containing tooth / regulation of heart rate by cardiac conduction / lateral plasma membrane / intercalated disc / membrane depolarization / cardiac muscle contraction / T-tubule / sodium ion transmembrane transport / regulation of heart rate / cellular response to calcium ion / cerebellum development / positive regulation of epithelial cell proliferation / sarcolemma / caveola / Z disc / scaffold protein binding / transmembrane transporter binding / calmodulin binding / protein domain specific binding / ubiquitin protein ligase binding / protein kinase binding / nucleolus / perinuclear region of cytoplasm / enzyme binding / cell surface / endoplasmic reticulum / nucleoplasm / 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 / Sodium ion transport-associated / Voltage-gated sodium channel alpha subunit, inactivation gate / Sodium ion transport-associated / SCN5A-like, C-terminal IQ motif / Voltage gated sodium channel, alpha subunit / Voltage-gated cation channel calcium and sodium / Voltage-dependent channel domain superfamily ...Voltage gated sodium channel, alpha-5 subunit / 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 / SCN5A-like, C-terminal IQ motif / Voltage gated sodium channel, alpha subunit / Voltage-gated cation channel calcium and sodium / Voltage-dependent channel domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Sodium channel protein type 5 subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsYan N / Li Z / Wu T
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32330052 China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Critical role of extracellular loops in differential modulations of TTX-sensitive and TTX-resistant Na channels.
Authors: Tong Wu / Xinyu Yang / Xueqin Jin / Nieng Yan / Zhangqiang Li /
Abstract: The cardiac voltage-gated sodium channel Na1.5 is resistant to tetrodotoxin (TTXr). Here, we report a cryo-electron microscopy (cryo-EM) structure of wild-type human Na1.5, coexpressed with the β1 ...The cardiac voltage-gated sodium channel Na1.5 is resistant to tetrodotoxin (TTXr). Here, we report a cryo-electron microscopy (cryo-EM) structure of wild-type human Na1.5, coexpressed with the β1 auxiliary subunit and treated with high-concentration TTX, at 3.4 Å resolution. Structural comparison reveals the molecular determinants for the distinct responses to TTX as well as β subunits between TTXr and TTX-sensitive (TTXs) Na channels. A conserved cation-π interaction between the guanidinium group of TTX and Tyr or Phe on the P2 helix in TTXs Na channels is lost in all TTXr subtypes owing to the replacement by Cys/Ser at the corresponding locus, explaining their differential TTX sensitivities. The β1 subunit is invisible in the EM map. Comparison of Na1.5 with Na1.7 and Na1.8, which are, respectively, TTXs and TTXr, identifies four sites on the extracellular loops (ECLs) that may account for their different β1-binding abilities. When the corresponding residues in TTXs Na1.7 are replaced with those from Na1.5, the modulatory effects of β1 on channel activation and inactivation are diminished. Consistently, β1 is absent in the 3D EM reconstruction of this Na1.7 mutant. Together with our previous structure-guided discovery that TTXr channels lack a Cys on the ECL for disulfide bond formation with β2 or β4, the structure-function relationship studies underscore the importance of the ECLs in the mechanistic distinctions between TTXs and TTXr Na channels. The ECLs may be further explored for the development of subtype-specific drugs.
History
DepositionJul 20, 2024-
Header (metadata) releaseAug 20, 2025-
Map releaseAug 20, 2025-
UpdateAug 20, 2025-
Current statusAug 20, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_60865.png

Downloads & links

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Map

FileDownload / File: emd_60865.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM map of Nav1.5 in complex with TTX
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.09 Å/pix.
x 240 pix.
= 261.84 Å		1.09 Å/pix.
x 240 pix.
= 261.84 Å		1.09 Å/pix.
x 240 pix.
= 261.84 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.091 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0171
Minimum - Maximum-0.11468148 - 0.17208734
Average (Standard dev.)0.00018900113 (±0.0052207597)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 261.84 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map 1

Fileemd_60865_half_map_1.map
AnnotationHalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2

Fileemd_60865_half_map_2.map
AnnotationHalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Nav1.5 in complex with TTX

EntireName: Nav1.5 in complex with TTX
Components
  • Complex: Nav1.5 in complex with TTX
    • Protein or peptide: Sodium channel protein type 5 subunit alpha
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (1R,5R,6R,7R,9S,11S,12S,13S,14S)-3-amino-14-(hydroxymethyl)-8,10-dioxa-2,4-diazatetracyclo[7.3.1.1~7,11~.0~1,6~]tetradec-3-ene-5,9,12,13,14-pentol (non-preferred name)
  • Ligand: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en

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Supramolecule #1: Nav1.5 in complex with TTX

SupramoleculeName: Nav1.5 in complex with TTX / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Sodium channel protein type 5 subunit alpha

MacromoleculeName: Sodium channel protein type 5 subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 231.743938 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MASWSHPQFE KGGGARGGSG GGSWSHPQFE KGFDYKDDDD KGTMANFLLP RGTSSFRRFT RESLAAIEKR MAEKQARGST TLQESREGL PEEEAPRPQL DLQASKKLPD LYGNPPQELI GEPLEDLDPF YSTQKTFIVL NKGKTIFRFS ATNALYVLSP F HPIRRAAV ...String:
MASWSHPQFE KGGGARGGSG GGSWSHPQFE KGFDYKDDDD KGTMANFLLP RGTSSFRRFT RESLAAIEKR MAEKQARGST TLQESREGL PEEEAPRPQL DLQASKKLPD LYGNPPQELI GEPLEDLDPF YSTQKTFIVL NKGKTIFRFS ATNALYVLSP F HPIRRAAV KILVHSLFNM LIMCTILTNC VFMAQHDPPP WTKYVEYTFT AIYTFESLVK ILARGFCLHA FTFLRDPWNW LD FSVIIMA YTTEFVDLGN VSALRTFRVL RALKTISVIS GLKTIVGALI QSVKKLADVM VLTVFCLSVF ALIGLQLFMG NLR HKCVRN FTALNGTNGS VEADGLVWES LDLYLSDPEN YLLKNGTSDV LLCGNSSDAG TCPEGYRCLK AGENPDHGYT SFDS FAWAF LALFRLMTQD CWERLYQQTL RSAGKIYMIF FMLVIFLGSF YLVNLILAVV AMAYEEQNQA TIAETEEKEK RFQEA MEML KKEHEALTIR GVDTVSRSSL EMSPLAPVNS HERRSKRRKR MSSGTEECGE DRLPKSDSED GPRAMNHLSL TRGLSR TSM KPRSSRGSIF TFRRRDLGSE ADFADDENST AGESESHHTS LLVPWPLRRT SAQGQPSPGT SAPGHALHGK KNSTVDC NG VVSLLGAGDP EATSPGSHLL RPVMLEHPPD TTTPSEEPGG PQMLTSQAPC VDGFEEPGAR QRALSAVSVL TSALEELE E SRHKCPPCWN RLAQRYLIWE CCPLWMSIKQ GVKLVVMDPF TDLTITMCIV LNTLFMALEH YNMTSEFEEM LQVGNLVFT GIFTAEMTFK IIALDPYYYF QQGWNIFDSI IVILSLMELG LSRMSNLSVL RSFRLLRVFK LAKSWPTLNT LIKIIGNSVG ALGNLTLVL AIIVFIFAVV GMQLFGKNYS ELRDSDSGLL PRWHMMDFFH AFLIIFRILC GEWIETMWDC MEVSGQSLCL L VFLLVMVI GNLVVLNLFL ALLLSSFSAD NLTAPDEDRE MNNLQLALAR IQRGLRFVKR TTWDFCCGLL RQRPQKPAAL AA QGQLPSC IATPYSPPPP ETEKVPPTRK ETRFEEGEQP GQGTPGDPEP VCVPIAVAES DTDDQEEDEE NSLGTEEESS KQQ ESQPVS GGPEAPPDSR TWSQVSATAS SEAEASASQA DWRQQWKAEP QAPGCGETPE DSCSEGSTAD MTNTAELLEQ IPDL GQDVK DPEDCFTEGC VRRCPCCAVD TTQAPGKVWW RLRKTCYHIV EHSWFETFII FMILLSSGAL AFEDIYLEER KTIKV LLEY ADKMFTYVFV LEMLLKWVAY GFKKYFTNAW CWLDFLIVDV SLVSLVANTL GFAEMGPIKS LRTLRALRPL RALSRF EGM RVVVNALVGA IPSIMNVLLV CLIFWLIFSI MGVNLFAGKF GRCINQTEGD LPLNYTIVNN KSQCESLNLT GELYWTK VK VNFDNVGAGY LALLQVATFK GWMDIMYAAV DSRGYEEQPQ WEYNLYMYIY FVIFIIFGSF FTLNLFIGVI IDNFNQQK K KLGGQDIFMT EEQKKYYNAM KKLGSKKPQK PIPRPLNKYQ GFIFDIVTKQ AFDVTIMFLI CLNMVTMMVE TDDQSPEKI NILAKINLLF VAIFTGECIV KLAALRHYYF TNSWNIFDFV VVILSIVGTV LSDIIQKYFF SPTLFRVIRL ARIGRILRLI RGAKGIRTL LFALMMSLPA LFNIGLLLFL VMFIYSIFGM ANFAYVKWEA GIDDMFNFQT FANSMLCLFQ ITTSAGWDGL L SPILNTGP PYCDPTLPNS NGSRGDCGSP AVGILFFTTY IIISFLIVVN MYIAIILENF SVATEESTEP LSEDDFDMFY EI WEKFDPE ATQFIEYSVL SDFADALSEP LRIAKPNQIS LINMDLPMVS GDRIHCMDIL FAFTKRVLGE SGEMDALKIQ MEE KFMAAN PSKISYEPIT TTLRRKHEEV SAMVIQRAFR RHLLQRSLKH ASFLFRQQAG SGLSEEDAPE REGLIAYVMS ENFS RPLGP PSSSSISSTS FPPSYDSVTR ATSDNLQVRG SDYSHSEDLA DFPPSPDRDR ESIV

UniProtKB: Sodium channel protein type 5 subunit alpha

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

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 2 / Number of copies: 9 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #3: (1R,5R,6R,7R,9S,11S,12S,13S,14S)-3-amino-14-(hydroxymethyl)-8,10-...

MacromoleculeName: (1R,5R,6R,7R,9S,11S,12S,13S,14S)-3-amino-14-(hydroxymethyl)-8,10-dioxa-2,4-diazatetracyclo[7.3.1.1~7,11~.0~1,6~]tetradec-3-ene-5,9,12,13,14-pentol (non-preferred name)
type: ligand / ID: 3 / Number of copies: 1 / Formula: 9SR
Molecular weightTheoretical: 319.268 Da
Chemical component information

ChemComp-9SR:
(1R,5R,6R,7R,9S,11S,12S,13S,14S)-3-amino-14-(hydroxymethyl)-8,10-dioxa-2,4-diazatetracyclo[7.3.1.1~7,11~.0~1,6~]tetradec-3-ene-5,9,12,13,14-pentol (non-preferred name) / toxin*YM

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Macromolecule #4: (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: 4 / Number of copies: 1 / 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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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 48.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 145139
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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