三元络合物
合作性
三元运算
降级(电信)
蛋白质降解
蛋白质水解
蛋白酶体
血浆蛋白结合
化学
生物物理学
泛素
计算生物学
细胞生物学
生物化学
计算机科学
生物
酶
电信
基因
程序设计语言
作者
Ryan P. Wurz,Huan Rui,Ken Dellamaggiore,Sudipa Ghimire-Rijal,Kaylee Choi,Kate Smither,Albert Amegadzie,Ning Chen,Xiaofen Li,Abhisek Banerjee,Qing Chen,Dane Mohl,Amit Vaish
标识
DOI:10.1038/s41467-023-39904-5
摘要
Abstract Targeted protein degradation via “hijacking” of the ubiquitin-proteasome system using proteolysis targeting chimeras (PROTACs) has evolved into a novel therapeutic modality. The design of PROTACs is challenging; multiple steps involved in PROTAC-induced degradation make it difficult to establish coherent structure-activity relationships. Herein, we characterize PROTAC-mediated ternary complex formation and degradation by employing von Hippel–Lindau protein (VHL) recruiting PROTACs for two different target proteins, SMARCA2 and BRD4. Ternary-complex attributes and degradation activity parameters are evaluated by varying components of the PROTAC’s architecture. Ternary complex binding affinity and cooperativity correlates well with degradation potency and initial rates of degradation. Additionally, we develop a ternary-complex structure modeling workflow to calculate the total buried surface area at the interface, which is in agreement with the measured ternary complex binding affinity. Our findings establish a predictive framework to guide the design of potent degraders.
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