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8XH8

Human Cx36/GJD2 (Ala14-deleted mutant) gap junction channel in porcine brain lipids

Summary for 8XH8
Entry DOI10.2210/pdb8xh8/pdb
EMDB information33270 33327 38344
DescriptorGap junction delta-2 protein, 1,2-DIMYRISTOYL-RAC-GLYCERO-3-PHOSPHOCHOLINE (2 entities in total)
Functional Keywordsconnexin 36, cx36, gap junction channel, membrane protein
Biological sourceHomo sapiens (human)
Total number of polymer chains12
Total formula weight496481.16
Authors
Cho, H.J.,Lee, H.H. (deposition date: 2023-12-17, release date: 2024-11-06)
Primary citationCho, H.J.,Chung, D.K.,Lee, H.H.
Mefloquine-induced conformational shift in Cx36 N-terminal helix leading to channel closure mediated by lipid bilayer.
Nat Commun, 15:9223-9223, 2024
Cited by
PubMed 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 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.
PubMed: 39455592
DOI: 10.1038/s41467-024-53587-6
PDB entries with the same primary citation
Experimental method
ELECTRON MICROSCOPY (2.72 Å)
Structure validation

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PDB entries from 2024-11-13

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