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- EMDB-38344: Human Cx36/GJD2 (Ala14-deleted mutant) gap junction channel in po... -

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Basic information

Entry
Database: EMDB / ID: EMD-38344
TitleHuman Cx36/GJD2 (Ala14-deleted mutant) gap junction channel in porcine brain lipids
Map dataCryo-EM density map, D6 symmetry
Sample
  • Complex: Human Cx36/GJD2 gap junction channel
    • 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 channel activity / Gap junction assembly / 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: 2.72 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 17, 2023-
Header (metadata) releaseNov 6, 2024-
Map releaseNov 6, 2024-
UpdateNov 27, 2024-
Current statusNov 27, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_38344.png

Downloads & links

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Map

FileDownload / File: emd_38344.map.gz / Format: CCP4 / Size: 125 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.)
0.86 Å/pix.
x 320 pix.
= 274.56 Å		0.86 Å/pix.
x 320 pix.
= 274.56 Å		0.86 Å/pix.
x 320 pix.
= 274.56 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.858 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.22
Minimum - Maximum-2.2791784 - 3.3463066
Average (Standard dev.)0.00095739024 (±0.09251064)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 274.56 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map A

Fileemd_38344_half_map_1.map
AnnotationHalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_38344_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

EntireName: Human Cx36/GJD2 gap junction channel
Components
  • Complex: Human Cx36/GJD2 gap junction channel
    • 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

SupramoleculeName: Human Cx36/GJD2 gap junction channel / 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-V320: connexin 36 (Ala14-deleted mutant) Residues S321-R322: linker Residues D323-K330: affinity tag (FLAG) Following regions are not modeled because of ambiguity of density map: ...Details: Residues M1-V320: connexin 36 (Ala14-deleted mutant) Residues S321-R322: linker Residues D323-K330: affinity tag (FLAG) Following regions are not modeled because of ambiguity of density map: Residues M1-S19, S100-I194, and W276-K330)
Number of copies: 12 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.305832 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGEWTILERL LEAVQQHSTM IGRILLTVVV IFRILIVAIV GETVYDDEQT MFVCNTLQPG CNQACYDRAF PISHIRYWVF QIIMVCTPS LCFITYSVHQ SAKQRERRYS TVFLALDRDP PESIGGPGGT GGGGSGGGKR EDKKLQNAIV NGVLQNTENT S KETEPDCL ...String:
MGEWTILERL LEAVQQHSTM IGRILLTVVV IFRILIVAIV GETVYDDEQT MFVCNTLQPG CNQACYDRAF PISHIRYWVF QIIMVCTPS LCFITYSVHQ SAKQRERRYS TVFLALDRDP PESIGGPGGT GGGGSGGGKR EDKKLQNAIV NGVLQNTENT S KETEPDCL EVKELTPHPS GLRTASKSKL RRQEGISRFY IIQVVFRNAL EIGFLVGQYF LYGFSVPGLY ECNRYPCIKE VE CYVSRPT EKTVFLVFMF AVSGICVVLN LAELNHLGWR KIKLAVRGAQ AKRKSIYEIR NKDLPRVSVP NFGRTQSSDS AYV SRDYKD DDDK

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: 72 / 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

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 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: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.72 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 63476
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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