泛素连接酶
泛素
药物发现
泛素蛋白连接酶类
小分子
蛋白质降解
计算生物学
酶
生物
药物开发
靶蛋白
细胞生物学
药品
DNA连接酶
生物化学
化学
基因
药理学
作者
Predrag Jevtić,Diane L. Haakonsen,Michael Rapé
标识
DOI:10.1016/j.chembiol.2021.04.002
摘要
Induced protein degradation accomplishes elimination, rather than inhibition, of pathological proteins. Key to the success of this novel therapeutic modality is the modification of proteins with ubiquitin chains, which is brought about by molecular glues or bivalent compounds that induce proximity between the target protein and an E3 ligase. The human genome encodes ∼600 E3 ligases that differ widely in their structures, catalytic mechanisms, modes of regulation, and physiological roles. While many of these enzymes hold great promise for drug discovery, few have been successfully engaged by small-molecule degraders. Here, we review E3 ligases that are being used for induced protein degradation. Based on these prior successes and our growing understanding of the biology and biochemistry of E3 ligases, we propose new ubiquitylation enzymes that can be harnessed for drug discovery to firmly establish induced protein degradation as a specific and efficient therapeutic approach.
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