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-Structure paper
タイトル | Apoptolidin family glycomacrolides target leukemia through inhibition of ATP synthase. |
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ジャーナル・号・ページ | Nat Chem Biol, Vol. 18, Issue 4, Page 360-367, Year 2022 |
掲載日 | 2021年12月2日 |
著者 | Benjamin J Reisman / Hui Guo / Haley E Ramsey / Madison T Wright / Bradley I Reinfeld / P Brent Ferrell / Gary A Sulikowski / W Kimryn Rathmell / Michael R Savona / Lars Plate / John L Rubinstein / Brian O Bachmann / |
PubMed 要旨 | Cancer cells have long been recognized to exhibit unique bioenergetic requirements. The apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene- ...Cancer cells have long been recognized to exhibit unique bioenergetic requirements. The apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene-transformed cells, yet their molecular mechanism remains uncertain. We used photoaffinity analogs of the apoptolidins to identify the F subcomplex of mitochondrial ATP synthase as the target of apoptolidin A. Cryogenic electron microscopy (cryo-EM) of apoptolidin and ammocidin-ATP synthase complexes revealed a novel shared mode of inhibition that was confirmed by deep mutational scanning of the binding interface to reveal resistance mutations which were confirmed using CRISPR-Cas9. Ammocidin A was found to suppress leukemia progression in vivo at doses that were tolerated with minimal toxicity. The combination of cellular, structural, mutagenesis, and in vivo evidence defines the mechanism of action of apoptolidin family glycomacrolides and establishes a path to address oxidative phosphorylation-dependent cancers. |
リンク | Nat Chem Biol / PubMed:34857958 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.1 - 4.2 Å |
構造データ | EMDB-23763, PDB-7md2: EMDB-23764, PDB-7md3: EMDB-23765: |
化合物 | ChemComp-ATP: ChemComp-MG: ChemComp-PO4: ChemComp-ZHD: ChemComp-ZH7: |
由来 |
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キーワード | HYDROLASE/HYDROLASE INHIBITOR / F1-ATPase / inhibitor / anti-cancer / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex / TRANSLOCASE |