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TitleMefloquine-induced conformational shift in Cx36 N-terminal helix leading to channel closure mediated by lipid bilayer.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 9223, Year 2024
Publish dateOct 25, 2024
AuthorsHwa-Jin Cho / Dong Kyu Chung / Hyung Ho Lee /
PubMed AbstractConnexin 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.
External linksNat Commun / PubMed:39455592 / PubMed Central
MethodsEM (single particle)
Resolution2.5 - 3.4 Å
Structure data

38318

8xgd

EMDB-38318, PDB-8xgd:
Human Cx36/GJD2 gap junction channel with pore-lining N-terminal helices in porcine brain lipids.
Method: EM (single particle) / Resolution: 2.5 Å

38319

8xge

EMDB-38319, PDB-8xge:
Human Cx36/GJD2 gap junction channel in porcine brain lipids.
Method: EM (single particle) / Resolution: 2.89 Å

38320

8xgf

EMDB-38320, PDB-8xgf:
Human Cx36/GJD2 gap junction channel in complex with arachidonic acid.
Method: EM (single particle) / Resolution: 2.95 Å

EMDB-38321: Human Cx36/GJD2 gap junction channel in complex with arachidonic acid (C1 symmetry).
Method: EM (single particle) / Resolution: 3.4 Å

38322

8xgg

EMDB-38322, PDB-8xgg:
Human Cx36/GJD2 gap junction channel in complex with 1-hexanol.
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-38326: Human Cx36/GJD2 gap junction channel in complex with mefloquine.
Method: EM (single particle) / Resolution: 3.2 Å

38327

8xgj

EMDB-38327, PDB-8xgj:
Human Cx36/GJD2 gap junction channel in complex with mefloquine.
Method: EM (single particle) / Resolution: 2.7 Å

38344

8xh8

EMDB-38344, PDB-8xh8:
Human Cx36/GJD2 (Ala14-deleted mutant) gap junction channel in porcine brain lipids
Method: EM (single particle) / Resolution: 2.72 Å

38345

8xh9

EMDB-38345, PDB-8xh9:
Human Cx36/GJD2 (Ala14 deletion mutant) gap junction channel prepared with mefloquine, showing no bound mefloquine
Method: EM (single particle) / Resolution: 2.58 Å

EMDB-38346: Human Cx36/GJD2 gap junction channel with pore-lining helices in porcine brain lipids (C1 symmetry)
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-38347: Human Cx36/GJD2 gap junction channel in porcine brain lipids (C1 symmetry)
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-38356: Human Cx36/GJD2 (Ala14-deleted mutant) gap junction channel in porcine brain lipids (C1 symmetry)
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-38357: Human Cx36/GJD2 (Ala14 deletion mutant) gap junction channel prepared with mefloquine, showing no bound mefloquine (C1 symmetry)
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-MC3:
1,2-DIMYRISTOYL-RAC-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-ACD:
ARACHIDONIC ACID

ChemComp-HE2:
HEXAN-1-OL

ChemComp-YMZ:
Mefloquine / medication*YM

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / connexin 36 / Cx36 / gap junction channel / GJD2 / arachidonic acid / hexanol / mefloquine

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