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- PDB-7tj9: Cryo-EM structure of the human Nax channel in complex with beta3 ... -

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Basic information

Entry
Database: PDB / ID: 7tj9
TitleCryo-EM structure of the human Nax channel in complex with beta3 solved in GDN
Components(Sodium channel ...) x 2
KeywordsTRANSPORT PROTEIN / Sodium Channel / NaV / Ion Channel
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
CHOLESTEROL / Chem-PEV / PALMITIC ACID / Chem-POV / Chem-Q7G / Sodium channel protein type 7 subunit alpha / Sodium channel regulatory subunit beta-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsNoland, C.L. / Kschonsak, M. / Ciferri, C. / Payandeh, J.
Funding support1items
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, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 30, 2022Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Sodium channel protein type 7 subunit alpha
B: Sodium channel subunit beta-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)234,36825
Polymers224,4082
Non-polymers9,96123
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Sodium channel ... , 2 types, 2 molecules AB

#1: Protein Sodium channel protein type 7 subunit alpha / / Putative voltage-gated sodium channel subunit alpha Nax / Sodium channel protein cardiac and ...Putative voltage-gated sodium channel subunit alpha Nax / Sodium channel protein cardiac and skeletal muscle subunit alpha / Sodium channel protein type VII subunit alpha


Mass: 199684.469 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SCN7A, SCN6A / Production host: Homo sapiens (human) / References: UniProt: Q01118
#2: Protein Sodium channel subunit beta-3 /


Mass: 24723.209 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SCN3B, KIAA1158 / Production host: Homo sapiens (human) / References: UniProt: Q9NY72

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Sugars , 2 types, 6 molecules

#3: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1 / Source method: obtained synthetically
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#7: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 5 types, 17 molecules

#4: Chemical ChemComp-PEV / (1S)-2-{[(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY)METHYL]ETHYL STEARATE / PHOSPHATIDYLETHANOLAMINE / 1-PALMITOYL-2-OLEOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE / Phosphatidylethanolamine


Mass: 720.012 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C39H78NO8P / Comment: POPE, phospholipid*YM
#5: Chemical ChemComp-POV / (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / POPC / POPC


Mass: 760.076 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C42H82NO8P / Comment: phospholipid*YM
#6: Chemical
ChemComp-PLM / PALMITIC ACID / Palmitic acid


Mass: 256.424 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C16H32O2
#8: Chemical ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O
#9: Chemical 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


Mass: 1165.315 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C56H92O25

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Details

Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Complex between human Nax and the Beta3 auxiliary subunit
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 1.067 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1420422 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00611231
ELECTRON MICROSCOPYf_angle_d0.60515147
ELECTRON MICROSCOPYf_dihedral_angle_d17.4331759
ELECTRON MICROSCOPYf_chiral_restr0.041716
ELECTRON MICROSCOPYf_plane_restr0.0051788

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