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. 2014 Oct 21;5(22):11252–11268. doi: 10.18632/oncotarget.2617

Fig. 9. Modelling of metformin-CLIC1 interaction.

Fig. 9

Schematic representation showing a possible mechanism of metformin's inhibition of CLIC1 wt, while it has no effect on R29A mutant. A) In the closed state of CLIC1 wt, the side chain of Arg29 makes an interaction that destabilizes the closed state. This facilitates the opening of the channel near the chloride reversal potential. B) Metformin displaces the guanidinium moiety of Arg29, stabilizing the closed state. In addition, the displaced Arg29 side chain may obstruct the channel pore. C) In the R29A mutant, the closed state is stable near the chloride reversal potential, as there is no Arg29 side chain to make the destabilizing interaction as it is replaced by Ala29. D) Metformin is free to bind to the guanidinium site in R29A, as it is unoccupied. It has no effect on channel opening at high membrane potentials.