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- EMDB-9782: Structure of human voltage-gated sodium channel Nav1.7 in complex... -

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Basic information

Entry
Database: EMDB / ID: EMD-9782
TitleStructure of human voltage-gated sodium channel Nav1.7 in complex with auxiliary beta subunits, ProTx-II and tetrodotoxin
Map data
Sample
  • Complex: Complex of human voltage-gated sodium channel Nav1.7 with auxiliary beta subunits, ProTx-II and tetrodotoxin
    • Protein or peptide: Sodium channel subunit beta-2
    • Protein or peptide: Sodium channel protein type 9 subunit alpha
    • Protein or peptide: Sodium channel subunit beta-1
  • Ligand: N-ACETYL-D-GLUCOSAMINEN-Acetylglucosamine
  • 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)
Function / homology
Function and homology information


corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / response to pyrethroid / detection of mechanical stimulus involved in sensory perception / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / membrane depolarization during Purkinje myocyte cell action potential / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / regulation of sodium ion transmembrane transporter activity / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / regulation of atrial cardiac muscle cell membrane depolarization ...corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / response to pyrethroid / detection of mechanical stimulus involved in sensory perception / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / membrane depolarization during Purkinje myocyte cell action potential / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / regulation of sodium ion transmembrane transporter activity / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / regulation of atrial cardiac muscle cell membrane depolarization / cardiac conduction / voltage-gated sodium channel complex / membrane depolarization during cardiac muscle cell action potential / positive regulation of sodium ion transport / node of Ranvier / cardiac muscle cell action potential involved in contraction / high voltage-gated calcium channel activity / locomotion / voltage-gated sodium channel activity / regulation of ventricular cardiac muscle cell membrane repolarization / sodium channel inhibitor activity / neuronal action potential propagation / Interaction between L1 and Ankyrins / sodium ion transport / behavioral response to pain / voltage-gated calcium channel complex / regulation of heart rate by cardiac conduction / Phase 0 - rapid depolarisation / detection of temperature stimulus involved in sensory perception of pain / calcium ion import across plasma membrane / membrane depolarization / sodium ion transmembrane transport / sodium channel regulator activity / intercalated disc / sensory perception of pain / cardiac muscle contraction / T-tubule / post-embryonic development / axon guidance / positive regulation of neuron projection development / Sensory perception of sweet, bitter, and umami (glutamate) taste / response to toxic substance / circadian rhythm / gene expression / nervous system development / response to heat / chemical synaptic transmission / perikaryon / transmembrane transporter binding / cell adhesion / inflammatory response / axon / synapse / extracellular region / plasma membrane
Similarity search - Function
Sodium channel subunit beta-1/beta-3 / Myelin P0 protein-related / 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 / Short calmodulin-binding motif containing conserved Ile and Gln residues. ...Sodium channel subunit beta-1/beta-3 / Myelin P0 protein-related / 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 / Short calmodulin-binding motif containing conserved Ile and Gln residues. / IQ motif, EF-hand binding site / Voltage-dependent channel domain superfamily / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Ion transport domain / Ion transport protein / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Sodium channel subunit beta-2 / Sodium channel subunit beta-1 / Sodium channel protein type 9 subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsShen H / Liu D / Lei J / Yan N
Funding support China, 5 items
OrganizationGrant numberCountry
Ministry of Science and Technology (China)2015CB910101 China
National Natural Science Foundation of China31621092 China
Ministry of Science and Technology (China)2016YFA0500402 China
National Natural Science Foundation of China81861138009 China
National Natural Science Foundation of China31630017 China
CitationJournal: Science / Year: 2019
Title: Structures of human Na1.7 channel in complex with auxiliary subunits and animal toxins.
Authors: Huaizong Shen / Dongliang Liu / Kun Wu / Jianlin Lei / Nieng Yan /
Abstract: Voltage-gated sodium channel Na1.7 represents a promising target for pain relief. Here we report the cryo-electron microscopy structures of the human Na1.7-β1-β2 complex bound to two combinations ...Voltage-gated sodium channel Na1.7 represents a promising target for pain relief. Here we report the cryo-electron microscopy structures of the human Na1.7-β1-β2 complex bound to two combinations of pore blockers and gating modifier toxins (GMTs), tetrodotoxin with protoxin-II and saxitoxin with huwentoxin-IV, both determined at overall resolutions of 3.2 angstroms. The two structures are nearly identical except for minor shifts of voltage-sensing domain II (VSD), whose S3-S4 linker accommodates the two GMTs in a similar manner. One additional protoxin-II sits on top of the S3-S4 linker in VSD The structures may represent an inactivated state with all four VSDs "up" and the intracellular gate closed. The structures illuminate the path toward mechanistic understanding of the function and disease of Na1.7 and establish the foundation for structure-aided development of analgesics.
History
DepositionJan 19, 2019-
Header (metadata) releaseFeb 27, 2019-
Map releaseFeb 27, 2019-
UpdateNov 6, 2019-
Current statusNov 6, 2019Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.06
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  • Surface level: 0.06
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  • Surface view with fitted model
  • Atomic models: PDB-6j8i
  • Surface level: 0.06
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6j8j
  • Surface level: 0.06
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_9782.png

Downloads & links

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Map

FileDownload / File: emd_9782.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.091 Å
Density
Contour LevelBy AUTHOR: 0.06 / Movie #1: 0.06
Minimum - Maximum-0.20992948 - 0.34865993
Average (Standard dev.)0.00077153894 (±0.009900675)
SymmetrySpace group: 1
Details

EMDB XML:

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

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0911.0911.091
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z261.840261.840261.840
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS240240240
D min/max/mean-0.2100.3490.001

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Supplemental data

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Sample components

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Entire : Complex of human voltage-gated sodium channel Nav1.7 with auxilia...

EntireName: Complex of human voltage-gated sodium channel Nav1.7 with auxiliary beta subunits, ProTx-II and tetrodotoxin
Components
  • Complex: Complex of human voltage-gated sodium channel Nav1.7 with auxiliary beta subunits, ProTx-II and tetrodotoxin
    • Protein or peptide: Sodium channel subunit beta-2
    • Protein or peptide: Sodium channel protein type 9 subunit alpha
    • Protein or peptide: Sodium channel subunit beta-1
  • Ligand: N-ACETYL-D-GLUCOSAMINEN-Acetylglucosamine
  • 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)

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Supramolecule #1: Complex of human voltage-gated sodium channel Nav1.7 with auxilia...

SupramoleculeName: Complex of human voltage-gated sodium channel Nav1.7 with auxiliary beta subunits, ProTx-II and tetrodotoxin
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: Sodium channel subunit beta-2

MacromoleculeName: Sodium channel subunit beta-2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.355859 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MHRDAWLPRP AFSLTGLSLF FSLVPPGRSM EVTVPATLNV LNGSDARLPC TFNSCYTVNH KQFSLNWTYQ ECNNCSEEMF LQFRMKIIN LKLERFQDRV EFSGNPSKYD VSVMLRNVQP EDEGIYNCYI MNPPDRHRGH GKIHLQVLME EPPERDSTVA V IVGASVGG ...String:
MHRDAWLPRP AFSLTGLSLF FSLVPPGRSM EVTVPATLNV LNGSDARLPC TFNSCYTVNH KQFSLNWTYQ ECNNCSEEMF LQFRMKIIN LKLERFQDRV EFSGNPSKYD VSVMLRNVQP EDEGIYNCYI MNPPDRHRGH GKIHLQVLME EPPERDSTVA V IVGASVGG FLAVVILVLM VVKCVRRKKE QKLSTDDLKT EEEGKTDGEG NPDDGAK

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Macromolecule #2: Sodium channel protein type 9 subunit alpha

MacromoleculeName: Sodium channel protein type 9 subunit alpha / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 231.211922 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MASWSHPQFE KGGGARGGSG GGSWSHPQFE KGFDYKDDDD KGTMAMLPPP GPQSFVHFTK QSLALIEQRI AERKSKEPKE EKKDDDEEA PKPSSDLEAG KQLPFIYGDI PPGMVSEPLE DLDPYYADKK TFIVLNKGKT IFRFNATPAL YMLSPFSPLR R ISIKILVH ...String:
MASWSHPQFE KGGGARGGSG GGSWSHPQFE KGFDYKDDDD KGTMAMLPPP GPQSFVHFTK QSLALIEQRI AERKSKEPKE EKKDDDEEA PKPSSDLEAG KQLPFIYGDI PPGMVSEPLE DLDPYYADKK TFIVLNKGKT IFRFNATPAL YMLSPFSPLR R ISIKILVH SLFSMLIMCT ILTNCIFMTM NNPPDWTKNV EYTFTGIYTF ESLVKILARG FCVGEFTFLR DPWNWLDFVV IV FAYLTEF VNLGNVSALR TFRVLRALKT ISVIPGLKTI VGALIQSVKK LSDVMILTVF CLSVFALIGL QLFMGNLKHK CFR NSLENN ETLESIMNTL ESEEDFRKYF YYLEGSKDAL LCGFSTDSGQ CPEGYTCVKI GRNPDYGYTS FDTFSWAFLA LFRL MTQDY WENLYQQTLR AAGKTYMIFF VVVIFLGSFY LINLILAVVA MAYKEQNQAN IEEAKQKELE FQQMLDRLKK EQEEA EAIA AAAAEYTSIR RSRIMGLSES SSETSKLSSK SAKERRNRRK KKNQKKLSSG EEKGDAEKLS KSESEDSIRR KSFHLG VEG HRRAHEKRLS TPNQSPLSIR GSLFSARRSS RTSLFSFKGR GRDIGSETEF ADDEHSIFGD NESRRGSLFV PHRPQER RS SNISQASRSP PMLPVNGKMH SAVDCNGVVS LVDGRSALML PNGQLLPEVI IDKATSDDSG TTNQIHKKRR CSSYLLSE D MLNDPNLRQR AMSRASILTN TVEELEESRQ KCPPWWYRFA HKFLIWNCSP YWIKFKKCIY FIVMDPFVDL AITICIVLN TLFMAMEHHP MTEEFKNVLA IGNLVFTGIF AAEMVLKLIA MDPYEYFQVG WNIFDSLIVT LSLVELFLAD VEGLSVLRSF RLLRVFKLA KSWPTLNMLI KIIGNSVGAL GNLTLVLAII VFIFAVVGMQ LFGKSYKECV CKINDDCTLP RWHMNDFFHS F LIVFRVLC GEWIETMWDC MEVAGQAMCL IVYMMVMVIG NLVVLNLFLA LLLSSFSSDN LTAIEEDPDA NNLQIAVTRI KK GINYVKQ TLREFILKAF SKKPKISREI RQAEDLNTKK ENYISNHTLA EMSKGHNFLK EKDKISGFGS SVDKHLMEDS DGQ SFIHNP SLTVTVPIAP GESDLENMNA EELSSDSDSE YSKVRLNRSS SSECSTVDNP LPGEGEEAEA EPMNSDEPEA CFTD GCVWR FSCCQVNIES GKGKIWWNIR KTCYKIVEHS WFESFIVLMI LLSSGALAFE DIYIERKKTI KIILEYADKI FTYIF ILEM LLKWIAYGYK TYFTNAWCWL DFLIVDVSLV TLVANTLGYS DLGPIKSLRT LRALRPLRAL SRFEGMRVVV NALIGA IPS IMNVLLVCLI FWLIFSIMGV NLFAGKFYEC INTTDGSRFP ASQVPNRSEC FALMNVSQNV RWKNLKVNFD NVGLGYL SL LQVATFKGWT IIMYAAVDSV NVDKQPKYEY SLYMYIYFVV FIIFGSFFTL NLFIGVIIDN FNQQKKKLGG QDIFMTEE Q KKYYNAMKKL GSKKPQKPIP RPGNKIQGCI FDLVTNQAFD ISIMVLICLN MVTMMVEKEG QSQHMTEVLY WINVVFIIL FTGECVLKLI SLRHYYFTVG WNIFDFVVVI ISIVGMFLAD LIETYFVSPT LFRVIRLARI GRILRLVKGA KGIRTLLFAL MMSLPALFN IGLLLFLVMF IYAIFGMSNF AYVKKEDGIN DMFNFETFGN SMICLFQITT SAGWDGLLAP ILNSKPPDCD P KKVHPGSS VEGDCGNPSV GIFYFVSYII ISFLVVVNMY IAVILENFSV ATEESTEPLS EDDFEMFYEV WEKFDPDATQ FI EFSKLSD FAAALDPPLL IAKPNKVQLI AMDLPMVSGD RIHCLDILFA FTKRVLGESG EMDSLRSQME ERFMSANPSK VSY EPITTT LKRKQEDVSA TVIQRAYRRY RLRQNVKNIS SIYIKDGDRD DDLLNKKDMA FDNVNENSSP EKTDATSSTT SPPS YDSVT KPDKEKYEQD RTEKEDKGKD SKESKK

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Macromolecule #3: Sodium channel subunit beta-1

MacromoleculeName: Sodium channel subunit beta-1 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.732115 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGRLLALVVG AALVSSACGG CVEVDSETEA VYGMTFKILC ISCKRRSETN AETFTEWTFR QKGTEEFVKI LRYENEVLQL EEDERFEGR VVWNGSRGTK DLQDLSIFIT NVTYNHSGDY ECHVYRLLFF ENYEHNTSVV KKIHIEVVDK ANRDMASIVS E IMMYVLIV ...String:
MGRLLALVVG AALVSSACGG CVEVDSETEA VYGMTFKILC ISCKRRSETN AETFTEWTFR QKGTEEFVKI LRYENEVLQL EEDERFEGR VVWNGSRGTK DLQDLSIFIT NVTYNHSGDY ECHVYRLLFF ENYEHNTSVV KKIHIEVVDK ANRDMASIVS E IMMYVLIV VLTIWLVAEM IYCYKKIAAA TETAAQENAS EYLAITSESK ENCTGVQVAE

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Macromolecule #4: N-ACETYL-D-GLUCOSAMINE

MacromoleculeName: N-ACETYL-D-GLUCOSAMINE / type: ligand / ID: 4 / Number of copies: 11 / Formula: NAG
Molecular weightTheoretical: 221.208 Da

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Macromolecule #5: (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: 5 / 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) / neurotoxin*YM / Tetrodotoxin

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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

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 48.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 263205

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