[English] 日本語
Yorodumi
- EMDB-35975: Structure of human Nav1.7 in complex with Hardwickii acid -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: EMDB / ID: EMD-35975
TitleStructure of human Nav1.7 in complex with Hardwickii acid
Map data
Sample
  • Complex: human Nav1.7 in complex with hardwickii acid
    • Protein or peptide: Sodium channel subunit beta-1
  • Protein or peptide: Sodium channel protein type 9 subunit alpha
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (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
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en
  • Ligand: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
KeywordsInhibitor complex. / MEMBRANE PROTEIN
Function / homology
Function and homology information


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 / 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 / regulation of atrial cardiac muscle cell membrane depolarization / cardiac conduction / voltage-gated sodium channel complex ...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 / 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 / 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 / perikaryon / transmembrane transporter binding / cell adhesion / inflammatory response / axon / extracellular region / plasma membrane
Similarity search - Function
Sodium channel subunit beta-1/beta-3 / 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 ...Sodium channel subunit beta-1/beta-3 / 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-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
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: 3.0 Å
AuthorsWu QR / Yan N
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32271252 China
CitationJournal: Nat Commun / Year: 2023
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
DepositionApr 19, 2023-
Header (metadata) releaseJun 14, 2023-
Map releaseJun 14, 2023-
UpdateJun 14, 2023-
Current statusJun 14, 2023Processing site: PDBj / Status: Released

-
Structure visualization

Supplemental images

emd_35975.png

Downloads & links

-
Map

FileDownload / File: emd_35975.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.0979 Å
Density
Contour LevelBy AUTHOR: 0.55
Minimum - Maximum-2.1853251 - 3.6765664
Average (Standard dev.)0.008615271 (±0.09392819)
SymmetrySpace group: 1
Details

EMDB XML:

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

-
Supplemental data

-
Half map: #2

Fileemd_35975_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: #1

Fileemd_35975_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Sample components

-
Entire : human Nav1.7 in complex with hardwickii acid

EntireName: human Nav1.7 in complex with hardwickii acid
Components
  • Complex: human Nav1.7 in complex with hardwickii acid
    • Protein or peptide: Sodium channel subunit beta-1
  • Protein or peptide: Sodium channel protein type 9 subunit alpha
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (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
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en
  • Ligand: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE

-
Supramolecule #1: human Nav1.7 in complex with hardwickii acid

SupramoleculeName: human Nav1.7 in complex with hardwickii acid / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 250 KDa

-
Macromolecule #1: Sodium channel protein type 9 subunit alpha

MacromoleculeName: Sodium channel protein type 9 subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 230.9225 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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

MacromoleculeName: Sodium channel subunit beta-1 / type: protein_or_peptide / ID: 2 / 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

-
Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

-
Macromolecule #5: (4~{a}~{R},5~{S},6~{R},8~{a}~{R})-5-[2-(furan-3-yl)ethyl]-5,6,8~{...

MacromoleculeName: (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
Molecular weightTheoretical: 316.435 Da
Chemical component information

ChemComp-UK0:
(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

-
Macromolecule #6: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 6 / Number of copies: 3 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

-
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

-
Macromolecule #8: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 8 / Number of copies: 10 / Formula: LPE
Molecular weightTheoretical: 510.708 Da
Chemical component information

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

-
Macromolecule #9: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 9 / Number of copies: 4 / Formula: PCW
Molecular weightTheoretical: 787.121 Da
Chemical component information

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

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

-
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

-
Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

33184

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 220477

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more