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MRC Mitochondrial Biology Unit


The results of a study from Professor Judy Hirst, Dr Hannah Bridges and co-workers in collaboration with McGill University and ImmunoMet Therapeutics Inc. have been published in Science.

Mitochondrial respiratory complex I is a major proposed cellular target enzyme of the anti-diabetic metformin, and for related biguanide drugs being developed for diverse medical applications.

100 years after metformin was first discovered, the team here have uncovered the molecular binding/interaction sites within complex I, including one that presents a novel type of drug-protein interaction. Their data can now start to explain in-vitro and in-vivo differences between biguanides and classical complex I inhibitors such as rotenone.

The research has revealed fundamental aspects in the understanding of biguanide interactions with complex I, which may play a central role in metformin’s therapeutic mechanism of action. The newly discovered drug-protein interaction mode can now also be considered when evaluating new and existing drugs for their on- or off-target mechanisms.

Full publication reference:

Bridges HR, Blaza JN, Yin Z, Chung I, Pollak MN, Hirst J.
Structural basis of mammalian respiratory complex I inhibition by medicinal biguanides.
Science, 379, 351-357. doi: 10.1126/science.ade3332