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

Next, using the alphaproteobacterial CI structure and its shared subunits with all known eukaryotic structures we propose the structure of CI from the First Eukaryotic Common Ancestor (FECA). This indicates that eukaryotic CI gained a new subunit every ~10-30 million years between FECA and LECA.

By comparing the structures of mitochondrial complex I across eukaryotic species and mapping them our best current model of the eukaryotic tree of life (yellow stars below indicate clades with complex I structures) we propose the structure of complex I from the Last Eukaryotic Common Ancestor (LECA)

New Review from the lab:
Respiratory complex I (CI) is composed of a conserved set of core subunits and additional accessory subunits that vary depending on the organism. Here, we categorize CI subunits from available structures to map the evolution of CI across eukaryotes. 1/n
tinyurl.com/txtrbfnw