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- EMDB-38357: Human Cx36/GJD2 (Ala14 deletion mutant) gap junction channel prep... -

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Basic information

Entry
Database: EMDB / ID: EMD-38357
TitleHuman Cx36/GJD2 (Ala14 deletion mutant) gap junction channel prepared with mefloquine, showing no bound mefloquine (C1 symmetry)
Map dataCryo-EM density map, C1 symmetry
Sample
  • Complex: Human Cx36/GJD2 (Ala14 deletion mutant) gap junction channel in brain lipids
Keywordsconnexin 36 / Cx36 / Gap Junction Channel / MEMBRANE PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 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 18, 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_38357.png

Downloads & links

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Map

FileDownload / File: emd_38357.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM density map, C1 symmetry
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.6 Å/pix.
x 360 pix.
= 216. Å		0.6 Å/pix.
x 360 pix.
= 216. Å		0.6 Å/pix.
x 360 pix.
= 216. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.6 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.70969677 - 0.9177248
Average (Standard dev.)0.0028321818 (±0.03981926)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 216.00002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map A

Fileemd_38357_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_38357_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 (Ala14 deletion mutant) gap junction channel in b...

EntireName: Human Cx36/GJD2 (Ala14 deletion mutant) gap junction channel in brain lipids
Components
  • Complex: Human Cx36/GJD2 (Ala14 deletion mutant) gap junction channel in brain lipids

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Supramolecule #1: Human Cx36/GJD2 (Ala14 deletion mutant) gap junction channel in b...

SupramoleculeName: Human Cx36/GJD2 (Ala14 deletion mutant) 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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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: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.8 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: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 51406
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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