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Cork-in-bottle mechanism of inhibitor binding to mammalian complex I.

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Serreli, Riccardo 
Cross, Jason B 
Di Francesco, M Emilia 
Marszalek, Joseph R 


Mitochondrial complex I (NADH:ubiquinone oxidoreductase), a major contributor of free energy for oxidative phosphorylation, is increasingly recognized as a promising drug target for ischemia-reperfusion injury, metabolic disorders, and various cancers. Several pharmacologically relevant but structurally unrelated small molecules have been identified as specific complex I inhibitors, but their modes of action remain unclear. Here, we present a 3.0-Å resolution cryo-electron microscopy structure of mammalian complex I inhibited by a derivative of IACS-010759, which is currently in clinical development against cancers reliant on oxidative phosphorylation, revealing its unique cork-in-bottle mechanism of inhibition. We combine structural and kinetic analyses to deconvolute cross-species differences in inhibition and identify the structural motif of a "chain" of aromatic rings as a characteristic that promotes inhibition. Our findings provide insights into the importance of π-stacking residues for inhibitor binding in the long substrate-binding channel in complex I and a guide for future biorational drug design.



3101 Biochemistry and Cell Biology, 32 Biomedical and Clinical Sciences, 31 Biological Sciences, 5 Development of treatments and therapeutic interventions, 1.1 Normal biological development and functioning, 1 Underpinning research, 5.1 Pharmaceuticals, Cancer

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American Association for the Advancement of Science (AAAS)
Medical Research Council (MC_U105663141)
MRC (MC_UU_00015/2)
Medical Research Council (MC_UU_00015/7)