Structural Basis of Mammalian Respiratory Complex I Inhibition by Medicinal Biguanides
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. One-Sentence SummaryBiguanides inhibit complex I by binding in the quinone channel, and exert an independent localized chaotropic effect.
Hirst Judy、Pollak Michael N.、Blaza James N.、Yin Zhan、Bridges Hannah R.、Chung Injae
MRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical CampusLady Davis Institute of the Jewish General Hospital and Department of Oncology, McGill UniversityMRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus||Department of Chemistry, The University of YorkMRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical CampusMRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical CampusMRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus
基础医学生物科学研究方法、生物科学研究技术生物化学
Hirst Judy,Pollak Michael N.,Blaza James N.,Yin Zhan,Bridges Hannah R.,Chung Injae.Structural Basis of Mammalian Respiratory Complex I Inhibition by Medicinal Biguanides[EB/OL].(2025-03-28)[2025-04-27].https://www.biorxiv.org/content/10.1101/2022.08.09.503333.点此复制
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