泛素连接酶
泛素
泛素蛋白连接酶类
小分子
蛋白酶体
蛋白质降解
细胞生物学
药物发现
DNA连接酶
靶蛋白
化学
计算生物学
生物化学
三元络合物
生物
基因
酶
作者
Daniel P. Bondeson,Blake E. Smith,George M. Burslem,Alexandru D. Buhimschi,John Hines,Saul Jaime‐Figueroa,Jing Wang,Brian D. Hamman,Alexey Ishchenko,Craig M. Crews
标识
DOI:10.1016/j.chembiol.2017.09.010
摘要
Summary
Inhibiting protein function selectively is a major goal of modern drug discovery. Here, we report a previously understudied benefit of small molecule proteolysis-targeting chimeras (PROTACs) that recruit E3 ubiquitin ligases to target proteins for their ubiquitination and subsequent proteasome-mediated degradation. Using promiscuous CRBN- and VHL-recruiting PROTACs that bind >50 kinases, we show that only a subset of bound targets is degraded. The basis of this selectivity relies on protein-protein interactions between the E3 ubiquitin ligase and the target protein, as illustrated by engaged proteins that are not degraded as a result of unstable ternary complexes with PROTAC-recruited E3 ligases. In contrast, weak PROTAC:target protein affinity can be stabilized by high-affinity target:PROTAC:ligase trimer interactions, leading to efficient degradation. This study highlights design guidelines for generating potent PROTACs as well as possibilities for degrading undruggable proteins immune to traditional small-molecule inhibitors.
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