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- EMDB-25920: Cryo-EM structure of the human Nax channel in complex with beta3 ... -

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Basic information

Entry
Database: EMDB / ID: EMD-25920
TitleCryo-EM structure of the human Nax channel in complex with beta3 solved in GDN
Map data
Sample
  • Complex: Complex between human Nax and the Beta3 auxiliary subunit
    • Protein or peptide: Sodium channel protein type 7 subunit alpha
    • Protein or peptide: Sodium channel subunit beta-3
  • Ligand: (1S)-2-{[(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY)METHYL]ETHYL STEARATE
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: PALMITIC ACID
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL
  • Ligand: 2-{[(4-O-alpha-D-glucopyranosyl-alpha-D-glucopyranosyl)oxy]methyl}-4-{[(3beta,9beta,14beta,17beta,25R)-spirost-5-en-3-yl]oxy}butyl 4-O-alpha-D-glucopyranosyl-alpha-D-glucopyranoside
Function / homology
Function and homology information


SA node cell action potential / regulation of ventricular cardiac muscle cell membrane depolarization / membrane depolarization during action potential / sodium ion homeostasis / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / regulation of sodium ion transmembrane transporter activity / atrial cardiac muscle cell action potential / regulation of atrial cardiac muscle cell membrane depolarization / voltage-gated monoatomic ion channel activity / voltage-gated sodium channel complex ...SA node cell action potential / regulation of ventricular cardiac muscle cell membrane depolarization / membrane depolarization during action potential / sodium ion homeostasis / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / regulation of sodium ion transmembrane transporter activity / atrial cardiac muscle cell action potential / regulation of atrial cardiac muscle cell membrane depolarization / voltage-gated monoatomic ion channel activity / voltage-gated sodium channel complex / membrane depolarization during cardiac muscle cell action potential / positive regulation of sodium ion transport / cellular homeostasis / cardiac muscle cell action potential involved in contraction / ventricular cardiac muscle cell action potential / voltage-gated sodium channel activity / regulation of monoatomic ion transmembrane transport / sodium channel inhibitor activity / Interaction between L1 and Ankyrins / positive regulation of heart rate / sodium ion transport / regulation of heart rate by cardiac conduction / Phase 0 - rapid depolarisation / glial cell projection / membrane depolarization / neuronal action potential / sodium ion transmembrane transport / sodium channel regulator activity / cardiac muscle contraction / muscle contraction / protein localization to plasma membrane / response to bacterium / Z disc / nervous system development / transmembrane transporter binding / axon / membrane / plasma membrane
Similarity search - Function
Voltage gated sodium channel, alpha-7 subunit / Sodium channel subunit beta-1/beta-3 / 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 / Immunoglobulin V-set domain / Immunoglobulin V-set domain ...Voltage gated sodium channel, alpha-7 subunit / Sodium channel subunit beta-1/beta-3 / 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 / 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 protein type 7 subunit alpha / Sodium channel regulatory subunit beta-3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsNoland CL / Kschonsak M / Ciferri C / Payandeh J
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2022
Title: Structure-guided unlocking of Na reveals a non-selective tetrodotoxin-sensitive cation channel.
Authors: Cameron L Noland / Han Chow Chua / Marc Kschonsak / Stephanie Andrea Heusser / Nina Braun / Timothy Chang / Christine Tam / Jia Tang / Christopher P Arthur / Claudio Ciferri / Stephan ...Authors: Cameron L Noland / Han Chow Chua / Marc Kschonsak / Stephanie Andrea Heusser / Nina Braun / Timothy Chang / Christine Tam / Jia Tang / Christopher P Arthur / Claudio Ciferri / Stephan Alexander Pless / Jian Payandeh /
Abstract: Unlike classical voltage-gated sodium (Na) channels, Na has been characterized as a voltage-insensitive, tetrodotoxin-resistant, sodium (Na)-activated channel involved in regulating Na homeostasis. ...Unlike classical voltage-gated sodium (Na) channels, Na has been characterized as a voltage-insensitive, tetrodotoxin-resistant, sodium (Na)-activated channel involved in regulating Na homeostasis. However, Na remains refractory to functional characterization in traditional heterologous systems. Here, to gain insight into its atypical physiology, we determine structures of the human Na channel in complex with the auxiliary β3-subunit. Na reveals structural alterations within the selectivity filter, voltage sensor-like domains, and pore module. We do not identify an extracellular Na-sensor or any evidence for a Na-based activation mechanism in Na. Instead, the S6-gate remains closed, membrane lipids fill the central cavity, and the domain III-IV linker restricts S6-dilation. We use protein engineering to identify three pore-wetting mutations targeting the hydrophobic S6-gate that unlock a robust voltage-insensitive leak conductance. This constitutively active Na-QTT channel construct is non-selective among monovalent cations, inhibited by extracellular calcium, and sensitive to classical Na channel blockers, including tetrodotoxin. Our findings highlight a functional diversity across the Na channel scaffold, reshape our understanding of Na physiology, and provide a template to demystify recalcitrant ion channels.
History
DepositionJan 14, 2022-
Header (metadata) releaseMar 30, 2022-
Map releaseMar 30, 2022-
UpdateMar 30, 2022-
Current statusMar 30, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25920.png

Downloads & links

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Map

FileDownload / File: emd_25920.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.1648 Å
Density
Contour LevelBy AUTHOR: 0.202
Minimum - Maximum-0.5761789 - 0.9689922
Average (Standard dev.)0.03624415 (±0.046607073)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 298.1888 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Complex between human Nax and the Beta3 auxiliary subunit

EntireName: Complex between human Nax and the Beta3 auxiliary subunit
Components
  • Complex: Complex between human Nax and the Beta3 auxiliary subunit
    • Protein or peptide: Sodium channel protein type 7 subunit alpha
    • Protein or peptide: Sodium channel subunit beta-3
  • Ligand: (1S)-2-{[(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY)METHYL]ETHYL STEARATE
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: PALMITIC ACID
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL
  • Ligand: 2-{[(4-O-alpha-D-glucopyranosyl-alpha-D-glucopyranosyl)oxy]methyl}-4-{[(3beta,9beta,14beta,17beta,25R)-spirost-5-en-3-yl]oxy}butyl 4-O-alpha-D-glucopyranosyl-alpha-D-glucopyranoside

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Supramolecule #1: Complex between human Nax and the Beta3 auxiliary subunit

SupramoleculeName: Complex between human Nax and the Beta3 auxiliary subunit
type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: Sodium channel protein type 7 subunit alpha

MacromoleculeName: Sodium channel protein type 7 subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 199.684469 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MWSHPQFEKG GGSGGGSGGS AWSHPQFEKF FSFFDYKDDD DKGGSGGDYK DDDDKMLASP EPKGLVPFTK ESFELIKQHI AKTHNEDHE EEDLKPTPDL EVGKKLPFIY GNLSQGMVSE PLEDVDPYYY KKKNTFIVLN KNRTIFRFNA ASILCTLSPF N CIRRTTIK ...String:
MWSHPQFEKG GGSGGGSGGS AWSHPQFEKF FSFFDYKDDD DKGGSGGDYK DDDDKMLASP EPKGLVPFTK ESFELIKQHI AKTHNEDHE EEDLKPTPDL EVGKKLPFIY GNLSQGMVSE PLEDVDPYYY KKKNTFIVLN KNRTIFRFNA ASILCTLSPF N CIRRTTIK VLVHPFFQLF ILISVLIDCV FMSLTNLPKW RPVLENTLLG IYTFEILVKL FARGVWAGSF SFLGDPWNWL DF SVTVFEV IIRYSPLDFI PTLQTARTLR ILKIIPLNQG LKSLVGVLIH CLKQLIGVII LTLFFLSIFS LIGMGLFMGN LKH KCFRWP QENENETLHN RTGNPYYIRE TENFYYLEGE RYALLCGNRT DAGQCPEGYV CVKAGINPDQ GFTNFDSFGW ALFA LFRLM AQDYPEVLYH QILYASGKVY MIFFVVVSFL FSFYMASLFL GILAMAYEEE KQRVGEISKK IEPKFQQTGK ELQEG NETD EAKTIQIEMK KRSPISTDTS LDVLEDATLR HKEELEKSKK ICPLYWYKFA KTFLIWNCSP CWLKLKEFVH RIIMAP FTD LFLIICIILN VCFLTLEHYP MSKQTNTLLN IGNLVFIGIF TAEMIFKIIA MHPYGYFQVG WNIFDSMIVF HGLIELC LA NVAGMALLRL FRMLRIFKLG KYWPTFQILM WSLSNSWVAL KDLVLLLFTF IFFSAAFGMK LFGKNYEEFV CHIDKDCQ L PRWHMHDFFH SFLNVFRILC GEWVETLWDC MEVAGQSWCI PFYLMVILIG NLLVLYLFLA LVSSFSSCKD VTAEENNEA KNLQLAVARI KKGINYVLLK ILCKTQNVPK DTMDHVNEVY VKEDISDHTL SELSNTQDFL KDKEKSSGTE KNATENESQS LIPSPSVSE TVPIASGESD IENLDNKEIQ SKSGDGGSKE KIKQSSSSEC STVDIAISEE EEMFYGGERS KHLKNGCRRG S SLGQISGA SKKGKIWQNI RKTCCKIVEN NWFKCFIGLV TLLSTGTLAF EDIYMDQRKT IKILLEYADM IFTYIFILEM LL KWMAYGF KAYFSNGWYR LDFVVVIVFC LSLIGKTREE LKPLISMKFL RPLRVLSQFE RMKVVVRALI KTTLPTLNVF LVC LMIWLI FSIMGVDLFA GRFYECIDPT SGERFPSSEV MNKSRCESLL FNESMLWENA KMNFDNVGNG FLSLLQVATF NGWI TIMNS AIDSVAVNIQ PHFEVNIYMY CYFINFIIFG VFLPLSMLIT VIIDNFNKHK IKLGGSNIFI TVKQRKQYRR LKKLM YEDS QRPVPRPLNK LQGFIFDVVT SQAFNVIVMV LICFQAIAMM IDTDVQSLQM SIALYWINSI FVMLYTMECI LKLIAF RCF YFTIAWNIFD FMVVIFSITG LCLPMTVGSY LVPPSLVQLI LLSRIIHMLR LGKGPKVFHN LMLPLMLSLP ALLNIIL LI FLVMFIYAVF GMYNFAYVKK EAGINDVSNF ETFGNSMLCL FQVAIFAGWD GMLDAIFNSK WSDCDPDKIN PGTQVRGD C GNPSVGIFYF VSYILISWLI IVNMYIVVVM EFLNIASKKK NKTLSEDDFR KFFQVWKRFD PDRTQYIDSS KLSDFAAAL DPPLFMAKPN KGQLIALDLP MAVGDRIHCL DILLAFTKRV MGQDVRMEKV VSEIESGFLL ANPFKITCEP ITTTLKRKQE AVSATIIQR AYKNYRLRRN DKNTSDIHMI DGDRDVHATK EGAYFDKAKE KSPIQSQI

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Macromolecule #2: Sodium channel subunit beta-3

MacromoleculeName: Sodium channel subunit beta-3 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.723209 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPAFNRLFPL ASLVLIYWVS VCFPVCVEVP SETEAVQGNP MKLRCISCMK REEVEATTVV EWFYRPEGGK DFLIYEYRNG HQEVESPFQ GRLQWNGSKD LQDVSITVLN VTLNDSGLYT CNVSREFEFE AHRPFVKTTR LIPLRVTEEA GEDFTSVVSE I MMYILLVF ...String:
MPAFNRLFPL ASLVLIYWVS VCFPVCVEVP SETEAVQGNP MKLRCISCMK REEVEATTVV EWFYRPEGGK DFLIYEYRNG HQEVESPFQ GRLQWNGSKD LQDVSITVLN VTLNDSGLYT CNVSREFEFE AHRPFVKTTR LIPLRVTEEA GEDFTSVVSE I MMYILLVF LTLWLLIEMI YCYRKVSKAE EAAQENASDY LAIPSENKEN SAVPVEE

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Macromolecule #4: (1S)-2-{[(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY...

MacromoleculeName: (1S)-2-{[(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY)METHYL]ETHYL STEARATE
type: ligand / ID: 4 / Number of copies: 3 / Formula: PEV
Molecular weightTheoretical: 720.012 Da
Chemical component information

ChemComp-PEV:
(1S)-2-{[(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY)METHYL]ETHYL STEARATE / POPE, phospholipid*YM / Phosphatidylethanolamine

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Macromolecule #5: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...

MacromoleculeName: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
type: ligand / ID: 5 / Number of copies: 3 / Formula: POV
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM / POPC

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Macromolecule #6: PALMITIC ACID

MacromoleculeName: PALMITIC ACID / type: ligand / ID: 6 / Number of copies: 8 / Formula: PLM
Molecular weightTheoretical: 256.424 Da
Chemical component information

ChemComp-PLM:
PALMITIC ACID / Palmitic acid

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Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / 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

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Macromolecule #8: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 8 / Number of copies: 2 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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Macromolecule #9: 2-{[(4-O-alpha-D-glucopyranosyl-alpha-D-glucopyranosyl)oxy]methyl...

MacromoleculeName: 2-{[(4-O-alpha-D-glucopyranosyl-alpha-D-glucopyranosyl)oxy]methyl}-4-{[(3beta,9beta,14beta,17beta,25R)-spirost-5-en-3-yl]oxy}butyl 4-O-alpha-D-glucopyranosyl-alpha-D-glucopyranoside
type: ligand / ID: 9 / Number of copies: 1 / Formula: Q7G
Molecular weightTheoretical: 1.165315 KDa
Chemical component information

ChemComp-Q7G:
2-{[(4-O-alpha-D-glucopyranosyl-alpha-D-glucopyranosyl)oxy]methyl}-4-{[(3beta,9beta,14beta,17beta,25R)-spirost-5-en-3-yl]oxy}butyl 4-O-alpha-D-glucopyranosyl-alpha-D-glucopyranoside

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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
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: 1.5 µm / Nominal defocus min: 0.5 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 1.067 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: Homology model with Nav1.4/Beta1 complex
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: PROJECTION MATCHING
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1420422

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