该药物二氮嗪通过抑制 AAA-ATP 酶 Drg1 来阻断核糖体的生物发生。
The drug diazaborine blocks ribosome biogenesis by inhibiting the AAA-ATPase Drg1.
机构信息
From the Institut für Molekulare Biowissenschaften, Karl-Franzens-Universität Graz, A-8010 Graz, Austria and.
出版信息
J Biol Chem. 2014 Feb 14;289(7):3913-22. doi: 10.1074/jbc.M113.536110. Epub 2013 Dec 26.
Abstract
The drug diazaborine is the only known inhibitor of ribosome biogenesis and specifically blocks large subunit formation in eukaryotic cells. However, the target of this drug and the mechanism of inhibition were unknown. Here we identify the AAA-ATPase Drg1 as a target of diazaborine. Inhibitor binding into the second AAA domain of Drg1 requires ATP loading and results in inhibition of ATP hydrolysis in this site. As a consequence the physiological activity of Drg1, i.e. the release of Rlp24 from pre-60S particles, is blocked, and further progression of cytoplasmic preribosome maturation is prevented. Our results identify the first target of an inhibitor of ribosome biogenesis and provide the mechanism of inhibition of a key step in large ribosomal subunit formation.
摘要
重氮硼烷是唯一已知的核糖体生物发生抑制剂，特异性地阻断真核细胞中大亚基的形成。然而，这种药物的靶点和抑制机制尚不清楚。在这里，我们将 AAA-ATPase Drg1 鉴定为重氮硼烷的靶标。抑制剂与 Drg1 的第二个 AAA 结构域结合需要 ATP 加载，并导致该位点的 ATP 水解抑制。因此，Drg1 的生理活性，即 Rlp24 从 pre-60S 颗粒中的释放被阻断，并且阻止细胞质前核糖体成熟的进一步进行。我们的结果确定了核糖体生物发生抑制剂的第一个靶标，并提供了大亚基形成的关键步骤的抑制机制。
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2
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3
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4
Assignment of protonation states in proteins and ligands: combining pKa prediction with hydrogen bonding network optimization.蛋白质和配体中质子化状态的分配：将pKa预测与氢键网络优化相结合。
Methods Mol Biol. 2012;819:405-21. doi: 10.1007/978-1-61779-465-0_25.
5
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6
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7
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