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- EMDB-80135: Cryo-EM structure of human Nav1.6 in complex with delta-paraponer... -

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Entry
Database: EMDB / ID: EMD-80135
TitleCryo-EM structure of human Nav1.6 in complex with delta-paraponeritoxin-Pc1a
Map data
Sample
  • Complex: Nav1.6-Pc1a
    • Protein or peptide: Sodium channel protein type 8 subunit alpha
    • Protein or peptide: Delta-paraponeritoxin-Pc1a
    • Protein or peptide: Sodium channel regulatory subunit beta-1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: CHOLESTEROL HEMISUCCINATE
KeywordsNav1.6 / voltage gated sodium channel / toxin / Pc1a / delta-paraponeritoxin-Pc1a / TRANSPORT PROTEIN / MEMBRANE PROTEIN
Function / homology
Function and homology information


corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / host cell postsynaptic membrane / regulation of atrial cardiac muscle cell membrane depolarization / sodium ion binding / cardiac conduction / membrane depolarization during cardiac muscle cell action potential / membrane depolarization during Purkinje myocyte cell action potential / membrane depolarization during action potential / positive regulation of sodium ion transport ...corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / host cell postsynaptic membrane / regulation of atrial cardiac muscle cell membrane depolarization / sodium ion binding / cardiac conduction / membrane depolarization during cardiac muscle cell action potential / membrane depolarization during Purkinje myocyte cell action potential / membrane depolarization during action potential / positive regulation of sodium ion transport / peripheral nervous system development / regulation of sodium ion transmembrane transport / axon initial segment / regulation of ventricular cardiac muscle cell membrane repolarization / host cell presynaptic membrane / cardiac muscle cell action potential involved in contraction / sodium channel inhibitor activity / voltage-gated sodium channel complex / node of Ranvier / podosome / neuronal action potential propagation / locomotion / voltage-gated sodium channel activity / Interaction between L1 and Ankyrins / sodium ion transport / Phase 0 - rapid depolarisation / regulation of heart rate by cardiac conduction / intercalated disc / sodium channel regulator activity / action potential / membrane depolarization / cardiac muscle contraction / myelination / T-tubule / axon guidance / sodium ion transmembrane transport / positive regulation of neuron projection development / Z disc / cell junction / Sensory perception of sweet, bitter, and umami (glutamate) taste / toxin activity / cytoplasmic vesicle / transmembrane transporter binding / perikaryon / cell adhesion / axon / extracellular region / membrane / plasma membrane
Similarity search - Function
Voltage gated sodium channel, alpha-8 subunit / Sodium channel subunit beta-1/beta-3 / 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 sodium channel, alpha-8 subunit / Sodium channel subunit beta-1/beta-3 / 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 / Short calmodulin-binding motif containing conserved Ile and Gln residues. / IQ motif, EF-hand binding site / IQ motif profile. / Voltage-dependent channel domain superfamily / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Ion transport domain / Ion transport protein / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Glycyl-poneratoxin / Sodium channel regulatory subunit beta-1 / Sodium channel protein type 8 subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human) / Paraponera clavata (insect)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsYang L / Fan X / Huang J / Yan N
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32330052, 32322039, 32271252, and 32501082 China
CitationJournal: Nature / Year: 2026
Title: Diverse binding poses of agonistic neurotoxins on human Na1.6.
Authors: Xiao Fan / Jian Huang / Lin Yang / Jiaofeng Chen / Huan Wang / Xiaoshuang Huang / Jinli Geng / Qinglin Wu / Yuzhen Xie / Fangzhou Lu / Qinmeng Guo / Zilin Shen / Xueqin Jin / Nieng Yan /
Abstract: Voltage-gated sodium (Na) channels are key targets of various venomous toxins. Deciphering the binding poses and mechanisms of action of representative toxins will help to dissect the functional ...Voltage-gated sodium (Na) channels are key targets of various venomous toxins. Deciphering the binding poses and mechanisms of action of representative toxins will help to dissect the functional mechanism of the channels and facilitate therapeutic development targeting Na channels. Here we present cryo-electron microscopy (cryo-EM) structures of distinct binding poses of three agonistic peptide toxins on the human Na1.6-β1 channel complex. The globular β-scorpion toxin Cn2 nestles between the extracellular segment of voltage-sensing domain (VSD) in the second repeat of the Na1.6 core α-unit (VSD) and the pore extracellular loops in the third repeat of the Na1.6 core α-unit (ECL), where it is stabilized by interactions with both protein regions and the branched N1372-glycan. Cone snail ι-conotoxin RXIA adopts an elongated conformation, spanning VSD and VSD to wrap around the shoulder of the pore domain (PD). The bullet ant-derived toxin δ-paraponeritoxin-Pc1a exists as a transmembrane helix that stands between VSD and PD. Our findings, corroborated by functional characterizations, illustrate the diversity in peptide toxin binding poses and mechanisms of action, link stabilization of the up state of VSD or VSD to channel activation, and provide clues to the rational design of selective Na channel modulators.
History
DepositionApr 6, 2026-
Header (metadata) releaseMay 20, 2026-
Map releaseMay 20, 2026-
UpdateJun 24, 2026-
Current statusJun 24, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_80135.png

Downloads & links

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Map

FileDownload / File: emd_80135.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 256 pix.
= 281.062 Å		1.1 Å/pix.
x 256 pix.
= 281.062 Å		1.1 Å/pix.
x 256 pix.
= 281.062 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0979 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.32
Minimum - Maximum-1.8790845 - 3.107101
Average (Standard dev.)0.0054150634 (±0.07258087)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 281.0624 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_80135_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_80135_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Nav1.6-Pc1a

EntireName: Nav1.6-Pc1a
Components
  • Complex: Nav1.6-Pc1a
    • Protein or peptide: Sodium channel protein type 8 subunit alpha
    • Protein or peptide: Delta-paraponeritoxin-Pc1a
    • Protein or peptide: Sodium channel regulatory subunit beta-1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: CHOLESTEROL HEMISUCCINATE

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Supramolecule #1: Nav1.6-Pc1a

SupramoleculeName: Nav1.6-Pc1a / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Sodium channel protein type 8 subunit alpha

MacromoleculeName: Sodium channel protein type 8 subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 225.520609 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAARLLAPPG PDSFKPFTPE SLANIERRIA ESKLKKPPKA DGSHREDDED SKPKPNSDLE AGKSLPFIYG DIPQGLVAVP LEDFDPYYL TQKTFVVLNR GKTLFRFSAT PALYILSPFN LIRRIAIKIL IHSVFSMIIM CTILTNCVFM TFSNPPDWSK N VEYTFTGI ...String:
MAARLLAPPG PDSFKPFTPE SLANIERRIA ESKLKKPPKA DGSHREDDED SKPKPNSDLE AGKSLPFIYG DIPQGLVAVP LEDFDPYYL TQKTFVVLNR GKTLFRFSAT PALYILSPFN LIRRIAIKIL IHSVFSMIIM CTILTNCVFM TFSNPPDWSK N VEYTFTGI YTFESLVKII ARGFCIDGFT FLRDPWNWLD FSVIMMAYIT EFVNLGNVSA LRTFRVLRAL KTISVIPGLK TI VGALIQS VKKLSDVMIL TVFCLSVFAL IGLQLFMGNL RNKCVVWPIN FNESYLENGT KGFDWEEYIN NKTNFYTVPG MLE PLLCGN SSDAGQCPEG YQCMKAGRNP NYGYTSFDTF SWAFLALFRL MTQDYWENLY QLTLRAAGKT YMIFFVLVIF VGSF YLVNL ILAVVAMAYE EQNQATLEEA EQKEAEFKAM LEQLKKQQEE AQAAAMATSA GTVSEDAIEE EGEEGGGSPR SSSEI SKLS SKSAKERRNR RKKRKQKELS EGEEKGDPEK VFKSESEDGM RRKAFRLPDN RIGRKFSIMN QSLLSIPGSP FLSRHN SKS SIFSFRGPGR FRDPGSENEF ADDEHSTVEE SEGRRDSLFI PIRARERRSS YSGYSGYSQG SRSSRIFPSL RRSVKRN ST VDCNGVVSLI GGPGSHIGGR LLPEATTEVE IKKKGPGSLL VSMDQLASYG RKDRINSIMS VVTNTLVEEL EESQRKCP P CWYKFANTFL IWECHPYWIK LKEIVNLIVM DPFVDLAITI CIVLNTLFMA MEHHPMTPQF EHVLAVGNLV FTGIFTAEM FLKLIAMDPY YYFQEGWNIF DGFIVSLSLM ELSLADVEGL SVLRSFRLLR VFKLAKSWPT LNMLIKIIGN SVGALGNLTL VLAIIVFIF AVVGMQLFGK SYKECVCKIN QDCELPRWHM HDFFHSFLIV FRVLCGEWIE TMWDCMEVAG QAMCLIVFMM V MVIGNLVV LNLFLALLLS SFSADNLAAT DDDGEMNNLQ ISVIRIKKGV AWTKLKVHAF MQAHFKQREA DEVKPLDELY EK KANCIAN HTGADIHRNG DFQKNGNGTT SGIGSSVEKY IIDEDHMSFI NNPNLTVRVP IAVGESDFEN LNTEDVSSES DPE GSKDKL DDTSSSEGST IDIKPEVEEV PVEQPEEYLD PDACFTEGCV QRFKCCQVNI EEGLGKSWWI LRKTCFLIVE HNWF ETFII FMILLSSGAL AFEDIYIEQR KTIRTILEYA DKVFTYIFIL EMLLKWTAYG FVKFFTNAWC WLDFLIVAVS LVSLI ANAL GYSELGAIKS LRTLRALRPL RALSRFEGMR VVVNALVGAI PSIMNVLLVC LIFWLIFSIM GVNLFAGKYH YCFNET SEI RFEIEDVNNK TECEKLMEGN NTEIRWKNVK INFDNVGAGY LALLQVATFK GWMDIMYAAV DSRKPDEQPK YEDNIYM YI YFVIFIIFGS FFTLNLFIGV IIDNFNQQKK KFGGQDIFMT EEQKKYYNAM KKLGSKKPQK PIPRPLNKIQ GIVFDFVT Q QAFDIVIMML ICLNMVTMMV ETDTQSKQME NILYWINLVF VIFFTCECVL KMFALRHYYF TIGWNIFDFV VVILSIVGM FLADIIEKYF VSPTLFRVIR LARIGRILRL IKGAKGIRTL LFALMMSLPA LFNIGLLLFL VMFIFSIFGM SNFAYVKHEA GIDDMFNFE TFGNSMICLF QITTSAGWDG LLLPILNRPP DCSLDKEHPG SGFKGDCGNP SVGIFFFVSY IIISFLIVVN M YIAIILEN FSVATEESAD PLSEDDFETF YEIWEKFDPD ATQFIEYCKL ADFADALEHP LRVPKPNTIE LIAMDLPMVS GD RIHCLDI LFAFTKRVLG DSGELDILRQ QMEERFVASN PSKVSYEPIT TTLRRKQEEV SAVVLQRAYR GHLARRGFIC KKT TSNKLE NGGTHREKKE STPSTASLPS YDSVTKPEKE KQQRAEEGRR ERAKRQKEVR ESKC

UniProtKB: Sodium channel protein type 8 subunit alpha

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Macromolecule #2: Delta-paraponeritoxin-Pc1a

MacromoleculeName: Delta-paraponeritoxin-Pc1a / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Paraponera clavata (insect)
Molecular weightTheoretical: 2.757363 KDa
Recombinant expressionOrganism: synthetic construct (others)
SequenceString:
FLPLLILGSL LMTPPVIQAI HDAQR(NH2)

UniProtKB: Glycyl-poneratoxin

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Macromolecule #3: Sodium channel regulatory subunit beta-1

MacromoleculeName: Sodium channel regulatory subunit beta-1 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 20.206018 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
GCVEVDSETE AVYGMTFKIL CISCKRRSET NAETFTEWTF RQKGTEEFVK ILRYENEVLQ LEEDERFEGR VVWNGSRGTK DLQDLSIFI TNVTYNHSGD YECHVYRLLF FENYEHNTSV VKKIHIEVVD KANRDMASIV SEIMMYVLIV VLTIWLVAEM I YCYKKIAA ATETA

UniProtKB: Sodium channel regulatory subunit beta-1

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 4 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

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Macromolecule #7: (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: 7 / 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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Macromolecule #8: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 8 / Number of copies: 3 / Formula: PCW
Molecular weightTheoretical: 787.121 Da
Chemical component information

ChemComp-PCW:
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipid*YM

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Macromolecule #9: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 9 / Number of copies: 2 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 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: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 191257
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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