德隆
泛素连接酶
蛋白质降解
蛋白酶体
计算生物学
泛素
靶蛋白
配体(生物化学)
遗传筛选
蛋白质水解
降级(电信)
生物
药物发现
化学
细胞生物学
遗传学
生物信息学
生物化学
表型
计算机科学
基因
受体
酶
电信
作者
Aisha Yesbolatova,Yusuke Tominari,Masato T. Kanemaki
标识
DOI:10.1016/j.ddtec.2018.11.001
摘要
Targeted protein degraders, known as proteolysis targeting chimeras (PROTACs), are drawing more attention as next-generation drugs to target currently undruggable proteins. As drug discovery of functional degraders involves time- and cost-consuming laborious processes, we propose employing a ligand-induced genetic degradation system to validate candidate proteins before degrader development. Genetic degradation mimics degrader treatment by depleting a degron-fused protein in the presence of a defined ligand. All genetic systems use a combination of a degron and defined ligand that enables a protein of interest fused with the degron to be recruited to an E3 ubiquitin ligase for ubiquitylation and subsequent degradation by the proteasome. However, these events are based on different principles and have different features. We review the dTAG, HaloTag-based, auxin-inducible degron (AID), and destabilizing domain (DD) systems and discuss a strategy for degrader discovery against novel target proteins.
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