Structural Basis of Mammalian Respiratory Complex I Inhibition by Medicinal Biguanides

Abstract

The molecular mode of action of metformin, a biguanide used widely in the treatment of diabetes, is incompletely characterized. Here we define the inhibitory drug-target interaction(s) of a model biguanide with mammalian respiratory complex I by combining cryo-electron microscopy and enzyme kinetics. We explain the unique selectivity of biguanide binding to different enzyme states. The primary inhibitory site is in an amphipathic region of the quinone-binding channel and an additional binding site is in a pocket on the intermembrane space side of the enzyme. An independent local chaotropic interaction, not previously described for any drug, displaces a portion of a key helix in the membrane domain. Our data provide a structural basis for biguanide action and enable rational design of novel medicinal biguanides.

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“…These data are in line with recent studies in which metformin has been shown to curb other metabolic pathways such as gluconeogenesis from lactate and glycerol [32] and fatty acid oxidation [67], or to target other mitochondrial enzymes, such as F 1 F o ATP synthase [33] and glycerophosphate dehydrogenase (mGPDH) [32,34,35]. Moreover, the recent release of mammalian CI structures binding IM1761092, a more complex and hydrophobic phenformin derivative that has a higher inhibitory activity on CI, revealed that biguanides are able to bind at least three sites in deactive CI explaining the non-competitive behaviour of these molecules [68], but also raising questions regarding their specificity and potency. Importantly, our results can contribute to explain the conflicting data obtained in clinical trials on the use of metformin as an anti-cancer drug for different neoplasias [20][21][22][23]27,29,30,60], which may express diverse levels of additional yet unknown molecular targets.…”