7b93
From Proteopedia
Cryo-EM structure of mitochondrial complex I from Mus musculus inhibited by IACS-2858 at 3.0 A
Structural highlights
FunctionNU3M_MOUSE Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) that is believed to belong to the minimal assembly required for catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone (By similarity). Publication Abstract from PubMedMitochondrial 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-A 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 pi-stacking residues for inhibitor binding in the long substrate-binding channel in complex I and a guide for future biorational drug design. Cork-in-bottle mechanism of inhibitor binding to mammalian complex I.,Chung I, Serreli R, Cross JB, Di Francesco ME, Marszalek JR, Hirst J Sci Adv. 2021 May 14;7(20):eabg4000. doi: 10.1126/sciadv.abg4000. Print 2021 May. PMID:33990335[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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