泛素连接酶
化学
蛋白质降解
蛋白质水解
电泳剂
配体(生物化学)
蛋白酶体
DNA连接酶
细胞生物学
脱氮酶
靶蛋白
信号转导衔接蛋白
生物化学
泛素
受体
酶
生物
基因
催化作用
作者
Xiaoyu Zhang,Lena Luukkonen,Christie L. Eissler,Vincent M. Crowley,Yu Yamashita,Michael A. Schafroth,Shota Kikuchi,David Weinstein,Kent T. Symons,Brian E. Nordin,Joe L Rodriguez,Thomas Wucherpfennig,Ludwig G Bauer,Melissa M. Dix,Dean Stamos,Todd M. Kinsella,Gabriel Simón,Kristen A. Baltgalvis,Benjamin F. Cravatt
摘要
Ligand-induced protein degradation has emerged as a compelling approach to promote the targeted elimination of proteins from cells by directing these proteins to the ubiquitin-proteasome machinery. So far, only a limited number of E3 ligases have been found to support ligand-induced protein degradation, reflecting a dearth of E3-binding compounds for proteolysis-targeting chimera (PROTAC) design. Here, we describe a functional screening strategy performed with a focused library of candidate electrophilic PROTACs to discover bifunctional compounds that degrade proteins in human cells by covalently engaging E3 ligases. Mechanistic studies revealed that the electrophilic PROTACs act through modifying specific cysteines in DCAF11, a poorly characterized E3 ligase substrate adaptor. We further show that DCAF11-directed electrophilic PROTACs can degrade multiple endogenous proteins, including FBKP12 and the androgen receptor, in human prostate cancer cells. Our findings designate DCAF11 as an E3 ligase capable of supporting ligand-induced protein degradation via electrophilic PROTACs.
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