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- EMDB-38319: Human Cx36/GJD2 gap junction channel in porcine brain lipids. -

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Basic information

Entry
Database: EMDB / ID: EMD-38319
TitleHuman Cx36/GJD2 gap junction channel in porcine brain lipids.
Map dataCryo-EM density map, D6 symmetry
Sample
  • Complex: Human Cx36/GJD2 gap junction channel in brain lipids
    • Protein or peptide: Gap junction delta-2 protein
  • Ligand: 1,2-DIMYRISTOYL-RAC-GLYCERO-3-PHOSPHOCHOLINE
Keywordsconnexin 36 / Cx36 / gap junction channel / membrane protein
Function / homology
Function and homology information


Electric Transmission Across Gap Junctions / connexin complex / Gap junction assembly / gap junction channel activity / neuronal action potential / visual perception / cell-cell signaling / chemical synaptic transmission / synapse / plasma membrane
Similarity search - Function
Gap junction delta-2 protein (Cx36) / Connexin / Connexin, N-terminal / Connexin, conserved site / Gap junction protein, cysteine-rich domain / Connexin, N-terminal domain superfamily / Connexin / Connexins signature 1. / Connexins signature 2. / Connexin homologues / Gap junction channel protein cysteine-rich domain
Similarity search - Domain/homology
Gap junction delta-2 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.89 Å
AuthorsCho HJ / Lee HH
Funding support Korea, Republic Of, 1 items
OrganizationGrant numberCountry
Samsung Science and Technology FoundationSSTF-BA2101-13 Korea, Republic Of
CitationJournal: Nat Commun / Year: 2024
Title: Mefloquine-induced conformational shift in Cx36 N-terminal helix leading to channel closure mediated by lipid bilayer.
Authors: Hwa-Jin Cho / Dong Kyu Chung / Hyung Ho Lee /
Abstract: Connexin 36 (Cx36) forms interneuronal gap junctions, establishing electrical synapses for rapid synaptic transmission. In disease conditions, inhibiting Cx36 gap junction channels (GJCs) is ...Connexin 36 (Cx36) forms interneuronal gap junctions, establishing electrical synapses for rapid synaptic transmission. In disease conditions, inhibiting Cx36 gap junction channels (GJCs) is beneficial, as it prevents abnormal synchronous neuronal firing and apoptotic signal propagation, mitigating seizures and progressive cell death. Here, we present cryo-electron microscopy structures of human Cx36 GJC in complex with known channel inhibitors, such as mefloquine, arachidonic acid, and 1-hexanol. Notably, these inhibitors competitively bind to the binding pocket of the N-terminal helices (NTH), inducing a conformational shift from the pore-lining NTH (PLN) state to the flexible NTH (FN) state. This leads to the obstruction of the channel pore by flat double-layer densities of lipids. These studies elucidate the molecular mechanisms of how Cx36 GJC can be modulated by inhibitors, providing valuable insights into potential therapeutic applications.
History
DepositionDec 15, 2023-
Header (metadata) releaseNov 6, 2024-
Map releaseNov 6, 2024-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_38319.png

Downloads & links

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Map

FileDownload / File: emd_38319.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM density map, D6 symmetry
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 300 pix.
= 250.2 Å		0.83 Å/pix.
x 300 pix.
= 250.2 Å		0.83 Å/pix.
x 300 pix.
= 250.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.834 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0015
Minimum - Maximum-0.023773452 - 0.037048656
Average (Standard dev.)0.00000006647323 (±0.0011470278)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 250.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map B

Fileemd_38319_half_map_1.map
AnnotationHalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_38319_half_map_2.map
AnnotationHalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human Cx36/GJD2 gap junction channel in brain lipids

EntireName: Human Cx36/GJD2 gap junction channel in brain lipids
Components
  • Complex: Human Cx36/GJD2 gap junction channel in brain lipids
    • Protein or peptide: Gap junction delta-2 protein
  • Ligand: 1,2-DIMYRISTOYL-RAC-GLYCERO-3-PHOSPHOCHOLINE

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Supramolecule #1: Human Cx36/GJD2 gap junction channel in brain lipids

SupramoleculeName: Human Cx36/GJD2 gap junction channel in brain lipids / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Gap junction delta-2 protein

MacromoleculeName: Gap junction delta-2 protein / type: protein_or_peptide / ID: 1
Details: Residues M1-V321: connexin 36 Residues S322-R323: linker Residues D324-K331: affinity tag (FLAG) Following regions are not modeled because of ambiguity of density map: Residues M1-H19, A102-E193, and W277-K331)
Number of copies: 12 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.37691 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGEWTILERL LEAAVQQHST MIGRILLTVV VIFRILIVAI VGETVYDDEQ TMFVCNTLQP GCNQACYDRA FPISHIRYWV FQIIMVCTP SLCFITYSVH QSAKQRERRY STVFLALDRD PPESIGGPGG TGGGGSGGGK REDKKLQNAI VNGVLQNTEN T SKETEPDC ...String:
MGEWTILERL LEAAVQQHST MIGRILLTVV VIFRILIVAI VGETVYDDEQ TMFVCNTLQP GCNQACYDRA FPISHIRYWV FQIIMVCTP SLCFITYSVH QSAKQRERRY STVFLALDRD PPESIGGPGG TGGGGSGGGK REDKKLQNAI VNGVLQNTEN T SKETEPDC LEVKELTPHP SGLRTASKSK LRRQEGISRF YIIQVVFRNA LEIGFLVGQY FLYGFSVPGL YECNRYPCIK EV ECYVSRP TEKTVFLVFM FAVSGICVVL NLAELNHLGW RKIKLAVRGA QAKRKSIYEI RNKDLPRVSV PNFGRTQSSD SAY VSRDYK DDDDK

UniProtKB: Gap junction delta-2 protein

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Macromolecule #2: 1,2-DIMYRISTOYL-RAC-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIMYRISTOYL-RAC-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 2 / Number of copies: 48 / Formula: MC3
Molecular weightTheoretical: 677.933 Da
Chemical component information

ChemComp-MC3:
1,2-DIMYRISTOYL-RAC-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 34.41 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.75 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7xkt

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.89 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 177311
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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