小脑
泛素连接酶
蛋白质组
计算生物学
泛素
泛素蛋白连接酶类
蛋白质降解
DNA连接酶
蛋白酶体
化学
生物
细胞生物学
生物化学
酶
基因
作者
Vladas Oleinikovas,Pablo Gaínza,Thomas Ryckmans,Bernhard Fasching,Nicolas H. Thomä
出处
期刊:Annual Review of Pharmacology and Toxicology
[Annual Reviews]
日期:2024-01-23
卷期号:64 (1): 291-312
被引量:7
标识
DOI:10.1146/annurev-pharmtox-022123-104147
摘要
Thalidomide and its derivatives are powerful cancer therapeutics that are among the best-understood molecular glue degraders (MGDs). These drugs selectively reprogram the E3 ubiquitin ligase cereblon (CRBN) to commit target proteins for degradation by the ubiquitin-proteasome system. MGDs create novel recognition interfaces on the surface of the E3 ligase that engage in induced protein-protein interactions with neosubstrates. Molecular insight into their mechanism of action opens exciting opportunities to engage a plethora of targets through a specific recognition motif, the G-loop. Our analysis shows that current CRBN-based MGDs can in principle recognize over 2,500 proteins in the human proteome that contain a G-loop. We review recent advances in tuning the specificity between CRBN and its MGD-induced neosubstrates and deduce a set of simple rules that govern these interactions. We conclude that rational MGD design efforts will enable selective degradation of many more proteins, expanding this therapeutic modality to more disease areas.
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