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bioRxiv · 10.1101/2022.08.09.503333

Structural Basis of Mammalian Respiratory Complex I Inhibition by Medicinal Biguanides

Bridges, H. R.·Blaza, J. N.·Yin, Z.·Chung, I.·Pollak, M. N.·Hirst, J.
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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. One-Sentence SummaryBiguanides inhibit complex I by binding in the quinone channel, and exert an independent localized chaotropic effect.

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Bridges, H. R., Blaza, J. N., Yin, Z., Chung, I., Pollak, M. N., Hirst, J.. 2022-08-09. Structural Basis of Mammalian Respiratory Complex I Inhibition by Medicinal Biguanides. https://doi.org/10.1101/2022.08.09.503333

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