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-Structure paper
タイトル | Cork-in-bottle mechanism of inhibitor binding to mammalian complex I. |
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ジャーナル・号・ページ | Sci Adv, Vol. 7, Issue 20, Year 2021 |
掲載日 | 2021年5月14日 |
![]() | Injae Chung / Riccardo Serreli / Jason B Cross / M Emilia Di Francesco / Joseph R Marszalek / Judy Hirst / ![]() ![]() |
PubMed 要旨 | 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. |
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手法 | EM (単粒子) |
解像度 | 3.04 Å |
構造データ | EMDB-12095, PDB-7b93: |
化合物 | ![]() ChemComp-SF4: ![]() ChemComp-PC1: ![]() ChemComp-3PE: ![]() ChemComp-FES: ![]() ChemComp-FMN: ![]() ChemComp-T2Q: ![]() ChemComp-CDL: ![]() ChemComp-ATP: ![]() ChemComp-NDP: ![]() ChemComp-ZN: ![]() ChemComp-EHZ: |
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