The state dependent binding and positive cooperativeity explain hydrophilic metformin's superior clinical properties and how it is able to effectively inhibit complex I even with low affinity. These results will help facilitate additional therapeutic developments against type 2 #diabetes

We show that hydrophobic biguanides also inhibit complex I in a state dependent manner but their inhibition can be explained using a competitive framework. Whereas, due to the trapping mechanism induced by quinone there is positive cooperativity between the binding of metformin and quinone. 3/n

Our data are consistent with a state-dependent inhibitor trapping mechanism, in which the hydrophilic metformin can only bind to complex I in its "open" state and then gets trapped on the complex due to quinone-binding-induced closing of the active site, trapping metformin in the Q-tunnel. 2/n