三元络合物
泛素连接酶
等温滴定量热法
溴尿嘧啶
化学
DNA连接酶
蛋白质降解
蛋白质水解
生物化学
小分子
血浆蛋白结合
生物物理学
突变
双功能
泛素蛋白连接酶类
泛素
细胞生物学
生物
DNA
突变
酶
组蛋白
催化作用
基因
作者
M.S. Gadd,Andrea Testa,Xavier Lucas,Kwok-Ho Chan,Wenzhang Chen,Douglas J. Lamont,Michael Zengerle,Alessio Ciulli
标识
DOI:10.1038/nchembio.2329
摘要
Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimeras) are bifunctional molecules that recruit a target protein in proximity to an E3 ubiquitin ligase to trigger protein degradation. Structural elucidation of the key ternary ligase-PROTAC-target species and its impact on target degradation selectivity remain elusive. We solved the crystal structure of Brd4 degrader MZ1 in complex with human VHL and the Brd4 bromodomain (Brd4BD2). The ligand folds into itself to allow formation of specific intermolecular interactions in the ternary complex. Isothermal titration calorimetry studies, supported by surface mutagenesis and proximity assays, are consistent with pronounced cooperative formation of ternary complexes with Brd4BD2. Structure-based-designed compound AT1 exhibits highly selective depletion of Brd4 in cells. Our results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into a stable and cooperative complex with an E3 ligase for selective degradation.
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