Distinct modes of N-terminal remodeling through a conserved inhibitor pocket in connexin-46/50

Single-particle cryo-EM shows that 2-APB and carbenoxolone perturb the hydrophobic N-terminal docking groove in native connexin-46/50 channels, yielding distinct N-terminal gating ensembles.

• Why it matters: Broad cross-isoform connexin inhibition is hard to control, and the structural basis for why chemically diverse inhibitors act across isoforms is not fully understood.
• What they did: Native connexin-46/50 gap junction channels were imaged by single-particle cryo-EM after treatment with 2-APB or carbenoxolone, and inhibitor-bound conformational ensembles were compared across connexins.
• The result: 2-APB produces ordered destabilized-open and gated N-terminal states with ligand- and lipid-associated densities, while CBX occupies the same groove but loses ordered N-terminal conformation, revealing a conserved pharmacologically sensitive pocket.