7r4d
Bovine complex I in the presence of IM1761092, deactive class vi (Composite map)Bovine complex I in the presence of IM1761092, deactive class vi (Composite map)
Structural highlights
FunctionQ7JAS9_BOVIN Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. Essential for the catalytic activity of complex I.[ARBA:ARBA00024297][RuleBase:RU003640] Publication Abstract from PubMedThe molecular mode of action of biguanides, including the drug metformin, which is widely used 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 interpret these data to explain the 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 the rational design of medicinal biguanides. Structural basis of mammalian respiratory complex I inhibition by medicinal biguanides.,Bridges HR, Blaza JN, Yin Z, Chung I, Pollak MN, Hirst J Science. 2023 Jan 27;379(6630):351-357. doi: 10.1126/science.ade3332. Epub 2023 , Jan 26. PMID:36701435[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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