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- PDB-8xgf: Human Cx36/GJD2 gap junction channel in complex with arachidonic acid. -

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Basic information

Entry
Database: PDB / ID: 8xgf
TitleHuman Cx36/GJD2 gap junction channel in complex with arachidonic acid.
ComponentsGap junction delta-2 protein
KeywordsMEMBRANE PROTEIN / connexin 36 / Gap Junction Channel / Cx36 / GJD2 / arachidonic acid
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
ARACHIDONIC ACID / 1,2-DIMYRISTOYL-RAC-GLYCERO-3-PHOSPHOCHOLINE / Gap junction delta-2 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.95 Å
AuthorsCho, H.J. / Lee, H.H.
Funding support Korea, Republic Of, 1items
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, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 6, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Gap junction delta-2 protein
J: Gap junction delta-2 protein
B: Gap junction delta-2 protein
C: Gap junction delta-2 protein
D: Gap junction delta-2 protein
E: Gap junction delta-2 protein
F: Gap junction delta-2 protein
G: Gap junction delta-2 protein
H: Gap junction delta-2 protein
I: Gap junction delta-2 protein
K: Gap junction delta-2 protein
L: Gap junction delta-2 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)509,123108
Polymers448,52312
Non-polymers60,60096
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Gap junction delta-2 protein / Connexin-36 / Cx36 / Gap junction alpha-9 protein


Mass: 37376.910 Da / Num. of mol.: 12
Source method: isolated from a genetically manipulated source
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, S101-I195, and G276-K331)
Source: (gene. exp.) Homo sapiens (human) / Gene: GJD2, GJA9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9UKL4
#2: Chemical...
ChemComp-MC3 / 1,2-DIMYRISTOYL-RAC-GLYCERO-3-PHOSPHOCHOLINE


Mass: 677.933 Da / Num. of mol.: 84 / Source method: obtained synthetically / Formula: C36H72NO8P / Comment: phospholipid*YM
#3: Chemical
ChemComp-ACD / ARACHIDONIC ACID


Mass: 304.467 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C20H32O2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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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: Human Cx36/GJD2 gap junction channel / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.95 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 68143 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00217340
ELECTRON MICROSCOPYf_angle_d0.68923160
ELECTRON MICROSCOPYf_dihedral_angle_d18.0633156
ELECTRON MICROSCOPYf_chiral_restr0.0382556
ELECTRON MICROSCOPYf_plane_restr0.0032808

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