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- EMDB-32475: Human Nav1.8 with A-803467, class III -

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ID or keywords:

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Basic information

Entry
Database: EMDB / ID: EMD-32475
TitleHuman Nav1.8 with A-803467, class III
Map data
Sample
  • Complex: sodium channel III
    • Protein or peptide: Sodium channel protein type 10 subunit alpha
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 5-(4-chlorophenyl)-~{N}-(3,5-dimethoxyphenyl)furan-2-carboxamide
  • Ligand: CHOLESTEROL
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine
Function / homology
Function and homology information


bundle of His cell action potential / AV node cell action potential / clathrin complex / membrane depolarization during action potential / regulation of atrial cardiac muscle cell membrane depolarization / sensory perception / voltage-gated sodium channel complex / voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / high voltage-gated calcium channel activity / voltage-gated sodium channel activity ...bundle of His cell action potential / AV node cell action potential / clathrin complex / membrane depolarization during action potential / regulation of atrial cardiac muscle cell membrane depolarization / sensory perception / voltage-gated sodium channel complex / voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / high voltage-gated calcium channel activity / voltage-gated sodium channel activity / regulation of monoatomic ion transmembrane transport / Interaction between L1 and Ankyrins / voltage-gated calcium channel complex / Phase 0 - rapid depolarisation / odontogenesis of dentin-containing tooth / calcium ion import across plasma membrane / sodium ion transmembrane transport / regulation of cardiac muscle contraction / regulation of heart rate / presynaptic membrane / transmembrane transporter binding / axon / glutamatergic synapse / extracellular exosome / plasma membrane
Similarity search - Function
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 / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Sodium channel protein type 10 subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsYan N / Pan XJ / Huang XS / Huang GX
Funding support China, 1 items
OrganizationGrant numberCountry
Other government China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2022
Title: Structural basis for high-voltage activation and subtype-specific inhibition of human Na1.8.
Authors: Xiaoshuang Huang / Xueqin Jin / Gaoxingyu Huang / Jian Huang / Tong Wu / Zhangqiang Li / Jiaofeng Chen / Fang Kong / Xiaojing Pan / Nieng Yan /
Abstract: The dorsal root ganglia-localized voltage-gated sodium (Na) channel Na1.8 represents a promising target for developing next-generation analgesics. A prominent characteristic of Na1.8 is the ...The dorsal root ganglia-localized voltage-gated sodium (Na) channel Na1.8 represents a promising target for developing next-generation analgesics. A prominent characteristic of Na1.8 is the requirement of more depolarized membrane potential for activation. Here we present the cryogenic electron microscopy structures of human Na1.8 alone and bound to a selective pore blocker, A-803467, at overall resolutions of 2.7 to 3.2 Å. The first voltage-sensing domain (VSD) displays three different conformations. Structure-guided mutagenesis identified the extracellular interface between VSD and the pore domain (PD) to be a determinant for the high-voltage dependence of activation. A-803467 was clearly resolved in the central cavity of the PD, clenching S6. Our structure-guided functional characterizations show that two nonligand binding residues, Thr397 on S6 and Gly1406 on S6, allosterically modulate the channel's sensitivity to A-803467. Comparison of available structures of human Na channels suggests the extracellular loop region to be a potential site for developing subtype-specific pore-blocking biologics.
History
DepositionDec 27, 2021-
Header (metadata) releaseAug 3, 2022-
Map releaseAug 3, 2022-
UpdateSep 21, 2022-
Current statusSep 21, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_32475.png

Downloads & links

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Map

FileDownload / File: emd_32475.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.0825 Å
Density
Contour LevelBy AUTHOR: 0.0217
Minimum - Maximum-0.043605037 - 0.08822126
Average (Standard dev.)0.00017008698 (±0.0030498023)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 259.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : sodium channel III

EntireName: sodium channel III
Components
  • Complex: sodium channel III
    • Protein or peptide: Sodium channel protein type 10 subunit alpha
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 5-(4-chlorophenyl)-~{N}-(3,5-dimethoxyphenyl)furan-2-carboxamide
  • Ligand: CHOLESTEROL
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine

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Supramolecule #1: sodium channel III

SupramoleculeName: sodium channel III / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: Sodium channel protein type 10 subunit alpha

MacromoleculeName: Sodium channel protein type 10 subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 220.9035 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MEFPIGSLET NNFRRFTPES LVEIEKQIAA KQGTKKAREK HREQKDQEEK PRPQLDLKAC NQLPKFYGEL PAELIGEPLE DLDPFYSTH RTFMVLNKGR TISRFSATRA LWLFSPFNLI RRTAIKVSVH SWFSLFITVT ILVNCVCMTR TDLPEKIEYV F TVIYTFEA ...String:
MEFPIGSLET NNFRRFTPES LVEIEKQIAA KQGTKKAREK HREQKDQEEK PRPQLDLKAC NQLPKFYGEL PAELIGEPLE DLDPFYSTH RTFMVLNKGR TISRFSATRA LWLFSPFNLI RRTAIKVSVH SWFSLFITVT ILVNCVCMTR TDLPEKIEYV F TVIYTFEA LIKILARGFC LNEFTYLRDP WNWLDFSVIT LAYVGTAIDL RGISGLRTFR VLRALKTVSV IPGLKVIVGA LI HSVKKLA DVTILTIFCL SVFALVGLQL FKGNLKNKCV KNDMAVNETT NYSSHRKPDI YINKRGTSDP LLCGNGSDSG HCP DGYICL KTSDNPDFNY TSFDSFAWAF LSLFRLMTQD SWERLYQQTL RTSGKIYMIF FVLVIFLGSF YLVNLILAVV TMAY EEQNQ ATTDEIEAKE KKFQEALEML RKEQEVLAAL GIDTTSLHSH NGSPLTSKNA SERRHRIKPR VSEGSTEDNK SPRSD PYNQ RRMSFLGLAS GKRRASHGSV FHFRSPGRDI SLPEGVTDDG VFPGDHESHR GSLLLGGGAG QQGPLPRSPL PQPSNP DSR HGEDEHQPPP TSELAPGAVD VSAFDAGQKK TFLSAEYLDE PFRAQRAMSV VSIITSVLEE LEESEQKCPP CLTSLSQ KY LIWDCCPMWV KLKTILFGLV TDPFAELTIT LCIVVNTIFM AMEHHGMSPT FEAMLQIGNI VFTIFFTAEM VFKIIAFD P YYYFQKKWNI FDCIIVTVSL LELGVAKKGS LSVLRSFRLL RVFKLAKSWP TLNTLIKIIG NSVGALGNLT IILAIIVFV FALVGKQLLG ENYRNNRKNI SAPHEDWPRW HMHDFFHSFL IVFRILCGEW IENMWACMEV GQKSICLILF LTVMVLGNLV VLNLFIALL LNSFFADNLT APEDDGEVNN LQVALARIQV FGHRTKQALC SFFSRSCPFP QPKAEPELVV KLPLSSSKAE N HIAANTAR GSSGGLQAPR GPRDEHSDFI ANPTVWVSVP IAEGESDLDD LEDDGGEDAQ SFQQEVIPKG QQEQLQQVER CG DHLTPRS PGTGTSSEDL APSLGETWKD ESVPQVPAEG VDDTSSSEGS TVDCLDPEEI LRKIPELADD LEEPDDCFTE GCI RHCPCC KLDTTKSPWD VGWQVRKTCY RIVEHSWFES FIIFMILLSS GSLAFEDYYL DQKPTVKALL EYTDRVFTFI FVFE MLLKW VAYGFKKYFT NAWCWLDFLI VNISLISLTA KILEYSEVAP IKALRTLRAL RPLRALSRFE GMRVVVDALV GAIPS IMNV LLVCLIFWLI FSIMGVNLFA GKFWRCINYT DGEFSLVPLS IVNNKSDCKI QNSTGSFFWV NVKVNFDNVA MGYLAL LQV ATFKGWMDIM YAAVDSREVN MQPKWEDNVY MYLYFVIFII FGGFFTLNLF VGVIIDNFNQ QKKKLGGQDI FMTEEQK KY YNAMKKLGSK KPQKPIPRPL NKFQGFVFDI VTRQAFDITI MVLICLNMIT MMVETDDQSE EKTKILGKIN QFFVAVFT G ECVMKMFALR QYYFTNGWNV FDFIVVVLSI ASLIFSAILK SLQSYFSPTL FRVIRLARIG RILRLIRAAK GIRTLLFAL MMSLPALFNI GLLLFLVMFI YSIFGMSSFP HVRWEAGIDD MFNFQTFANS MLCLFQITTS AGWDGLLSPI LNTGPPYCDP NLPNSNGTR GDCGSPAVGI IFFTTYIIIS FLIMVNMYIA VILENFNVAT EESTEPLSED DFDMFYETWE KFDPEATQFI T FSALSDFA DTLSGPLRIP KPNRNILIQM DLPLVPGDKI HCLDILFAFT KNVLGESGEL DSLKANMEEK FMATNLSKSS YE PIATTLR WKQEDISATV IQKAYRSYVL HRSMALSNTP CVPRAEEEAA SLPDEGFVAF TANENCVLPD KSETASATSF PPS YESVTR GLSDRVNMRT SSSIQNEDEA TSMELIAPGP

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 3 / 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 #4: 5-(4-chlorophenyl)-~{N}-(3,5-dimethoxyphenyl)furan-2-carboxamide

MacromoleculeName: 5-(4-chlorophenyl)-~{N}-(3,5-dimethoxyphenyl)furan-2-carboxamide
type: ligand / ID: 4 / Number of copies: 1 / Formula: 95T
Molecular weightTheoretical: 357.788 Da
Chemical component information

ChemComp-95T:
5-(4-chlorophenyl)-~{N}-(3,5-dimethoxyphenyl)furan-2-carboxamide

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Macromolecule #5: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 5 / Number of copies: 5 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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Macromolecule #6: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 6 / Number of copies: 7 / 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 #7: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 7 / Number of copies: 12 / Formula: LPE
Molecular weightTheoretical: 510.708 Da
Chemical component information

ChemComp-LPE:
1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE

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Macromolecule #8: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phospho...

MacromoleculeName: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine
type: ligand / ID: 8 / Number of copies: 1 / Formula: P5S
Molecular weightTheoretical: 792.075 Da
Chemical component information

ChemComp-P5S:
O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine / Phosphatidylserine

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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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.5 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 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: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 274882

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