Mefloquine-induced conformational shift in Cx36 N-terminal helix leading to channel closure mediated by lipid bilayer.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
25 Oct 2024
25 Oct 2024
Historique:
received:
09
04
2024
accepted:
15
10
2024
medline:
26
10
2024
pubmed:
26
10
2024
entrez:
25
10
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39455592
doi: 10.1038/s41467-024-53587-6
pii: 10.1038/s41467-024-53587-6
doi:
Substances chimiques
Mefloquine
TML814419R
Connexins
0
Lipid Bilayers
0
Gap Junction delta-2 Protein
0
Arachidonic Acid
27YG812J1I
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
9223Informations de copyright
© 2024. The Author(s).
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