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-Structure paper
Title | Cork-in-bottle mechanism of inhibitor binding to mammalian complex I. |
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Journal, issue, pages | Sci Adv, Vol. 7, Issue 20, Year 2021 |
Publish date | May 14, 2021 |
Authors | Injae Chung / Riccardo Serreli / Jason B Cross / M Emilia Di Francesco / Joseph R Marszalek / Judy Hirst / |
PubMed Abstract | 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- ...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. |
External links | Sci Adv / PubMed:33990335 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.04 Å |
Structure data | EMDB-12095, PDB-7b93: |
Chemicals | ChemComp-SF4: ChemComp-PC1: ChemComp-3PE: ChemComp-FES: ChemComp-FMN: ChemComp-T2Q: ChemComp-CDL: ChemComp-ATP: ChemComp-NDP: ChemComp-ZN: ChemComp-EHZ: |
Source |
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Keywords | OXIDOREDUCTASE / Inhibitor / Ubiquinone / Complex I |