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Open data
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Basic information
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Title | Structure of human Nav1.7 in complex with Hardwickii acid | |||||||||
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![]() | Inhibitor complex. / MEMBRANE PROTEIN | |||||||||
Function / homology | ![]() corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / detection of mechanical stimulus involved in sensory perception / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / regulation of sodium ion transmembrane transporter activity / membrane depolarization during Purkinje myocyte cell action potential / regulation of atrial cardiac muscle cell membrane depolarization / cardiac conduction / membrane depolarization during cardiac muscle cell action potential ...corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / detection of mechanical stimulus involved in sensory perception / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / regulation of sodium ion transmembrane transporter activity / membrane depolarization during Purkinje myocyte cell action potential / regulation of atrial cardiac muscle cell membrane depolarization / cardiac conduction / 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 / regulation of ventricular cardiac muscle cell membrane repolarization / voltage-gated sodium channel complex / sodium channel inhibitor activity / locomotion / neuronal action potential propagation / Interaction between L1 and Ankyrins / voltage-gated sodium channel activity / sodium ion transport / Phase 0 - rapid depolarisation / behavioral response to pain / regulation of heart rate by cardiac conduction / detection of temperature stimulus involved in sensory perception of pain / membrane depolarization / intercalated disc / sodium ion transmembrane transport / sodium channel regulator activity / cardiac muscle contraction / sensory perception of pain / T-tubule / post-embryonic development / axon guidance / circadian rhythm / response to toxic substance / Sensory perception of sweet, bitter, and umami (glutamate) taste / positive regulation of neuron projection development / perikaryon / transmembrane transporter binding / cell adhesion / inflammatory response / axon / extracellular region / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.0 Å | |||||||||
![]() | Wu QR / Yan N | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Structural mapping of Na1.7 antagonists. Authors: Qiurong Wu / Jian Huang / Xiao Fan / Kan Wang / Xueqin Jin / Gaoxingyu Huang / Jiaao Li / Xiaojing Pan / Nieng Yan / ![]() ![]() Abstract: Voltage-gated sodium (Na) channels are targeted by a number of widely used and investigational drugs for the treatment of epilepsy, arrhythmia, pain, and other disorders. Despite recent advances in ...Voltage-gated sodium (Na) channels are targeted by a number of widely used and investigational drugs for the treatment of epilepsy, arrhythmia, pain, and other disorders. Despite recent advances in structural elucidation of Na channels, the binding mode of most Na-targeting drugs remains unknown. Here we report high-resolution cryo-EM structures of human Na1.7 treated with drugs and lead compounds with representative chemical backbones at resolutions of 2.6-3.2 Å. A binding site beneath the intracellular gate (site BIG) accommodates carbamazepine, bupivacaine, and lacosamide. Unexpectedly, a second molecule of lacosamide plugs into the selectivity filter from the central cavity. Fenestrations are popular sites for various state-dependent drugs. We show that vinpocetine, a synthetic derivative of a vinca alkaloid, and hardwickiic acid, a natural product with antinociceptive effect, bind to the III-IV fenestration, while vixotrigine, an analgesic candidate, penetrates the IV-I fenestration of the pore domain. Our results permit building a 3D structural map for known drug-binding sites on Na channels summarized from the present and previous structures. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 59.6 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 18.5 KB 18.5 KB | Display Display | ![]() |
Images | ![]() | 67 KB | ||
Others | ![]() ![]() | 59.4 MB 59.4 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 827.8 KB | Display | ![]() |
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Full document | ![]() | 827.4 KB | Display | |
Data in XML | ![]() | 12.4 KB | Display | |
Data in CIF | ![]() | 14.6 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8j4fMC ![]() 8i5bC ![]() 8i5gC ![]() 8i5xC ![]() 8i5yC ![]() 8s9bC ![]() 8s9cC 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: 1.0979 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_35975_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_35975_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
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Sample components
-Entire : human Nav1.7 in complex with hardwickii acid
Entire | Name: human Nav1.7 in complex with hardwickii acid |
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Components |
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-Supramolecule #1: human Nav1.7 in complex with hardwickii acid
Supramolecule | Name: human Nav1.7 in complex with hardwickii acid / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #2 |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 250 KDa |
-Macromolecule #1: Sodium channel protein type 9 subunit alpha
Macromolecule | Name: Sodium channel protein type 9 subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 230.9225 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: WSHPQFEKGG GARGGSGGGS WSHPQFEKGF DYKDDDDKGT MAMLPPPGPQ SFVHFTKQSL ALIEQRIAER KSKEPKEEKK DDDEEAPKP SSDLEAGKQL PFIYGDIPPG MVSEPLEDLD PYYADKKTFI VLNKGKTIFR FNATPALYML SPFSPLRRIS I KILVHSLF ...String: WSHPQFEKGG GARGGSGGGS WSHPQFEKGF DYKDDDDKGT MAMLPPPGPQ SFVHFTKQSL ALIEQRIAER KSKEPKEEKK DDDEEAPKP SSDLEAGKQL PFIYGDIPPG MVSEPLEDLD PYYADKKTFI VLNKGKTIFR FNATPALYML SPFSPLRRIS I KILVHSLF SMLIMCTILT NCIFMTMNNP PDWTKNVEYT FTGIYTFESL VKILARGFCV GEFTFLRDPW NWLDFVVIVF AY LTEFVNL GNVSALRTFR VLRALKTISV IPGLKTIVGA LIQSVKKLSD VMILTVFCLS VFALIGLQLF MGNLKHKCFR NSL ENNETL ESIMNTLESE EDFRKYFYYL EGSKDALLCG FSTDSGQCPE GYTCVKIGRN PDYGYTSFDT FSWAFLALFR LMTQ DYWEN LYQQTLRAAG KTYMIFFVVV IFLGSFYLIN LILAVVAMAY EEQNQANIEE AKQKELEFQQ MLDRLKKEQE EAEAI AAAA AEYTSIRRSR IMGLSESSSE TSKLSSKSAK ERRNRRKKKN QKKLSSGEEK GDAEKLSKSE SEDSIRRKSF HLGVEG HRR AHEKRLSTPN QSPLSIRGSL FSARRSSRTS LFSFKGRGRD IGSETEFADD EHSIFGDNES RRGSLFVPHR PQERRSS NI SQASRSPPML PVNGKMHSAV DCNGVVSLVD GRSALMLPNG QLLPEVIIDK ATSDDSGTTN QIHKKRRCSS YLLSEDML N DPNLRQRAMS RASILTNTVE ELEESRQKCP PWWYRFAHKF LIWNCSPYWI KFKKCIYFIV MDPFVDLAIT ICIVLNTLF MAMEHHPMTE EFKNVLAIGN LVFTGIFAAE MVLKLIAMDP YEYFQVGWNI FDSLIVTLSL VELFLADVEG LSVLRSFRLL RVFKLAKSW PTLNMLIKII GNSVGALGNL TLVLAIIVFI FAVVGMQLFG KSYKECVCKI NDDCTLPRWH MNDFFHSFLI V FRVLCGEW IETMWDCMEV AGQAMCLIVY MMVMVIGNLV VLNLFLALLL SSFSSDNLTA IEEDPDANNL QIAVTRIKKG IN YVKQTLR EFILKAFSKK PKISREIRQA EDLNTKKENY ISNHTLAEMS KGHNFLKEKD KISGFGSSVD KHLMEDSDGQ SFI HNPSLT VTVPIAPGES DLENMNAEEL SSDSDSEYSK VRLNRSSSSE CSTVDNPLPG EGEEAEAEPM NSDEPEACFT DGCV WRFSC CQVNIESGKG KIWWNIRKTC YKIVEHSWFE SFIVLMILLS SGALAFEDIY IERKKTIKII LEYADKIFTY IFILE MLLK WIAYGYKTYF TNAWCWLDFL IVDVSLVTLV ANTLGYSDLG PIKSLRTLRA LRPLRALSRF EGMRVVVNAL IGAIPS IMN VLLVCLIFWL IFSIMGVNLF AGKFYECINT TDGSRFPASQ VPNRSECFAL MNVSQNVRWK NLKVNFDNVG LGYLSLL QV ATFKGWTIIM YAAVDSVNVD KQPKYEYSLY MYIYFVVFII FGSFFTLNLF IGVIIDNFNQ QKKKLGGQDI FMTEEQKK Y YNAMKKLGSK KPQKPIPRPG NKIQGCIFDL VTNQAFDISI MVLICLNMVT MMVEKEGQSQ HMTEVLYWIN VVFIILFTG ECVLKLISLR HYYFTVGWNI FDFVVVIISI VGMFLADLIE TYFVSPTLFR VIRLARIGRI LRLVKGAKGI RTLLFALMMS LPALFNIGL LLFLVMFIYA IFGMSNFAYV KKEDGINDMF NFETFGNSMI CLFQITTSAG WDGLLAPILN SKPPDCDPKK V HPGSSVEG DCGNPSVGIF YFVSYIIISF LVVVNMYIAV ILENFSVATE ESTEPLSEDD FEMFYEVWEK FDPDATQFIE FS KLSDFAA ALDPPLLIAK PNKVQLIAMD LPMVSGDRIH CLDILFAFTK RVLGESGEMD SLRSQMEERF MSANPSKVSY EPI TTTLKR KQEDVSATVI QRAYRRYRLR QNVKNISSIY IKDGDRDDDL LNKKDMAFDN VNENSSPEKT DATSSTTSPP SYDS VTKPD KEKYEQDRTE KEDKGKDSKE SKK |
-Macromolecule #2: Sodium channel subunit beta-1
Macromolecule | Name: Sodium channel subunit beta-1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 24.732115 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: 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 |
-Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 5 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-Macromolecule #5: (4~{a}~{R},5~{S},6~{R},8~{a}~{R})-5-[2-(furan-3-yl)ethyl]-5,6,8~{...
Macromolecule | Name: (4~{a}~{R},5~{S},6~{R},8~{a}~{R})-5-[2-(furan-3-yl)ethyl]-5,6,8~{a}-trimethyl-3,4,4~{a},6,7,8-hexahydronaphthalene-1-carboxylic acid type: ligand / ID: 5 / Number of copies: 1 / Formula: UK0 |
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Molecular weight | Theoretical: 316.435 Da |
Chemical component information | ![]() ChemComp-UK0: |
-Macromolecule #6: CHOLESTEROL HEMISUCCINATE
Macromolecule | Name: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 6 / Number of copies: 3 / Formula: Y01 |
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Molecular weight | Theoretical: 486.726 Da |
Chemical component information | ![]() ChemComp-Y01: |
-Macromolecule #7: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]sp...
Macromolecule | Name: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en type: ligand / ID: 7 / Number of copies: 1 / Formula: 9Z9 |
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Molecular weight | Theoretical: 544.805 Da |
Chemical component information | ![]() ChemComp-9Z9: |
-Macromolecule #8: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE
Macromolecule | Name: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 8 / Number of copies: 10 / Formula: LPE |
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Molecular weight | Theoretical: 510.708 Da |
Chemical component information | ![]() ChemComp-LPE: |
-Macromolecule #9: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
Macromolecule | Name: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 9 / Number of copies: 4 / Formula: PCW |
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Molecular weight | Theoretical: 787.121 Da |
Chemical component information | ![]() ChemComp-PCW: |
-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
Startup model | Type of model: EMDB MAP EMDB ID: |
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Final reconstruction | Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 220477 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |