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Open data
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Basic information
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Title | Human Nav1.8 with A-803467, class II | |||||||||
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Function / homology | ![]() bundle of His cell action potential / AV node cell action potential / clathrin complex / regulation of atrial cardiac muscle cell membrane depolarization / sensory perception / voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / membrane depolarization during action potential / cardiac muscle cell action potential involved in contraction / voltage-gated sodium channel complex / regulation of monoatomic ion transmembrane transport ...bundle of His cell action potential / AV node cell action potential / clathrin complex / regulation of atrial cardiac muscle cell membrane depolarization / sensory perception / voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / membrane depolarization during action potential / cardiac muscle cell action potential involved in contraction / voltage-gated sodium channel complex / regulation of monoatomic ion transmembrane transport / Interaction between L1 and Ankyrins / voltage-gated sodium channel activity / Phase 0 - rapid depolarisation / odontogenesis of dentin-containing tooth / regulation of cardiac muscle contraction / sodium ion transmembrane transport / regulation of heart rate / presynaptic membrane / transmembrane transporter binding / axon / glutamatergic synapse / extracellular exosome / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.2 Å | |||||||||
![]() | Yan N / Pan XJ / Huang XS / Huang GX | |||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 49.3 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 13.3 KB 13.3 KB | Display Display | ![]() |
Images | ![]() | 77.6 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7welMC ![]() 7we4C ![]() 7wfrC ![]() 7wfwC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 1.0825 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
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Sample components
-Entire : sodium channel II
Entire | Name: sodium channel II |
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Components |
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-Supramolecule #1: sodium channel II
Supramolecule | Name: sodium channel II / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
Recombinant expression | Organism: ![]() |
-Macromolecule #1: Sodium channel protein type 10 subunit alpha
Macromolecule | Name: Sodium channel protein type 10 subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 220.9035 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: 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 |
-Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 3 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-Macromolecule #4: 5-(4-chlorophenyl)-~{N}-(3,5-dimethoxyphenyl)furan-2-carboxamide
Macromolecule | Name: 5-(4-chlorophenyl)-~{N}-(3,5-dimethoxyphenyl)furan-2-carboxamide type: ligand / ID: 4 / Number of copies: 1 / Formula: 95T |
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Molecular weight | Theoretical: 357.788 Da |
Chemical component information | ![]() ChemComp-95T: |
-Macromolecule #5: CHOLESTEROL
Macromolecule | Name: CHOLESTEROL / type: ligand / ID: 5 / Number of copies: 5 / Formula: CLR |
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Molecular weight | Theoretical: 386.654 Da |
Chemical component information | ![]() ChemComp-CLR: |
-Macromolecule #6: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
Macromolecule | Name: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 6 / Number of copies: 7 / Formula: PCW |
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Molecular weight | Theoretical: 787.121 Da |
Chemical component information | ![]() ChemComp-PCW: |
-Macromolecule #7: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE
Macromolecule | Name: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 7 / Number of copies: 12 / Formula: LPE |
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Molecular weight | Theoretical: 510.708 Da |
Chemical component information | ![]() ChemComp-LPE: |
-Macromolecule #8: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phospho...
Macromolecule | Name: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine type: ligand / ID: 8 / Number of copies: 2 / Formula: P5S |
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Molecular weight | Theoretical: 792.075 Da |
Chemical component information | ![]() ChemComp-P5S: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.5 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 141848 |
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Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |