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基本情報
登録情報 | データベース: PDB / ID: 7md3 | |||||||||||||||||||||||||||
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タイトル | The F1 region of apoptolidin-bound Saccharomyces cerevisiae ATP synthase | |||||||||||||||||||||||||||
![]() | (ATP synthase subunit ...) x 4 | |||||||||||||||||||||||||||
![]() | HYDROLASE/HYDROLASE INHIBITOR / F1-ATPase / inhibitor / anti-cancer / HYDROLASE / TRANSLOCASE / HYDROLASE-HYDROLASE INHIBITOR complex | |||||||||||||||||||||||||||
機能・相同性 | ![]() : / : / : / : / : / : / proton motive force-driven ATP synthesis / proton-transporting ATP synthase complex, catalytic core F(1) / H+-transporting two-sector ATPase / proton-transporting ATPase activity, rotational mechanism ...: / : / : / : / : / : / proton motive force-driven ATP synthesis / proton-transporting ATP synthase complex, catalytic core F(1) / H+-transporting two-sector ATPase / proton-transporting ATPase activity, rotational mechanism / proton-transporting ATP synthase activity, rotational mechanism / proton motive force-driven mitochondrial ATP synthesis / ADP binding / mitochondrial inner membrane / ATP hydrolysis activity / mitochondrion / ATP binding 類似検索 - 分子機能 | |||||||||||||||||||||||||||
生物種 | ![]() ![]() | |||||||||||||||||||||||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.3 Å | |||||||||||||||||||||||||||
![]() | Guo, H. / Rubinstein, J.L. | |||||||||||||||||||||||||||
資金援助 | ![]() ![]()
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![]() | ![]() タイトル: Apoptolidin family glycomacrolides target leukemia through inhibition of ATP synthase. 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 ...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 / ![]() ![]() 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. | |||||||||||||||||||||||||||
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構造ビューア | 分子: ![]() ![]() |
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要素
-ATP synthase subunit ... , 4種, 8分子 ABCDEFGH
#1: タンパク質 | 分子量: 55007.402 Da / 分子数: 3 / 由来タイプ: 天然 / 由来: (天然) ![]() ![]() #2: タンパク質 | 分子量: 51181.082 Da / 分子数: 3 / 由来タイプ: 天然 / 由来: (天然) ![]() ![]() 参照: UniProt: A0A6A5PX46, H+-transporting two-sector ATPase #3: タンパク質 | | 分子量: 30657.160 Da / 分子数: 1 / 由来タイプ: 天然 / 由来: (天然) ![]() ![]() #4: タンパク質 | | 分子量: 6618.359 Da / 分子数: 1 / 由来タイプ: 天然 / 由来: (天然) ![]() ![]() |
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-非ポリマー , 4種, 8分子 ![](data/chem/img/ATP.gif)
![](data/chem/img/MG.gif)
![](data/chem/img/PO4.gif)
![](data/chem/img/ZH7.gif)
![](data/chem/img/MG.gif)
![](data/chem/img/PO4.gif)
![](data/chem/img/ZH7.gif)
#5: 化合物 | #6: 化合物 | #7: 化合物 | ChemComp-PO4 / | #8: 化合物 | ChemComp-ZH7 / ( | |
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