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- EMDB-25919: Cryo-EM structure of the human Nax channel in complex with beta3 ... -

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Basic information

Entry
Database: EMDB / ID: EMD-25919
TitleCryo-EM structure of the human Nax channel in complex with beta3 solved in nanodiscs
Map data
Sample
  • Complex: Complex of human Nax with 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
KeywordsSodium Channel / NaV / Ion Channel / METAL TRANSPORT
Function / homology
Function and homology information


regulation of sodium ion transmembrane transporter activity / SA node cell action potential / regulation of ventricular cardiac muscle cell membrane depolarization / sodium ion homeostasis / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / atrial cardiac muscle cell action potential / voltage-gated monoatomic ion channel activity / regulation of atrial cardiac muscle cell membrane depolarization / membrane depolarization during cardiac muscle cell action potential / positive regulation of sodium ion transport ...regulation of sodium ion transmembrane transporter activity / SA node cell action potential / regulation of ventricular cardiac muscle cell membrane depolarization / sodium ion homeostasis / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / atrial cardiac muscle cell action potential / voltage-gated monoatomic ion channel activity / regulation of atrial cardiac muscle cell membrane depolarization / membrane depolarization during cardiac muscle cell action potential / positive regulation of sodium ion transport / sodium channel inhibitor activity / ventricular cardiac muscle cell action potential / membrane depolarization during action potential / voltage-gated sodium channel complex / cardiac muscle cell action potential involved in contraction / cellular homeostasis / regulation of monoatomic ion transmembrane transport / Interaction between L1 and Ankyrins / voltage-gated sodium channel activity / positive regulation of heart rate / sodium ion transport / Phase 0 - rapid depolarisation / regulation of heart rate by cardiac conduction / membrane depolarization / glial cell projection / neuronal action potential / sodium channel regulator activity / sodium ion transmembrane transport / 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 / Sodium ion transport-associated / Voltage-gated sodium channel alpha subunit, inactivation gate / 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 / Sodium ion transport-associated / Voltage-gated sodium channel alpha subunit, inactivation gate / 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: 3.2 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-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25919.png

Downloads & links

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Map

FileDownload / File: emd_25919.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 360 pix.
= 305.64 Å		0.85 Å/pix.
x 360 pix.
= 305.64 Å		0.85 Å/pix.
x 360 pix.
= 305.64 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.849 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.161
Minimum - Maximum-0.60963124 - 1.2724068
Average (Standard dev.)-0.008226747 (±0.036057573)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 305.63998 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Complex of human Nax with the Beta3 auxiliary subunit

EntireName: Complex of human Nax with the Beta3 auxiliary subunit
Components
  • Complex: Complex of human Nax with 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

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Supramolecule #1: Complex of human Nax with the Beta3 auxiliary subunit

SupramoleculeName: Complex of human Nax with the Beta3 auxiliary subunit / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Details: Sample is in MSPD1E3D1 nanodiscs with a 3:1:1 mix of POPC:POPE:POPG
Source (natural)Organism: 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

UniProtKB: Sodium channel protein type 7 subunit alpha

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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

UniProtKB: Sodium channel regulatory subunit beta-3

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Macromolecule #3: (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: 3 / 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

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Macromolecule #4: (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: 4 / 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

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Macromolecule #5: PALMITIC ACID

MacromoleculeName: PALMITIC ACID / type: ligand / ID: 5 / Number of copies: 6 / Formula: PLM
Molecular weightTheoretical: 256.424 Da
Chemical component information

ChemComp-PLM:
PALMITIC ACID

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #7: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 7 / Number of copies: 1 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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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
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 0.972 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

9024


Details: Map low-pass filtered to 20 Angstrom resolution and density outside nanodisc deleted
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1238338
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: PROJECTION MATCHING

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