Methods to direct the degradation of protein targets with proximity-inducing molecules that coopt the cellular degradation machinery are advancing in leaps and bounds, and diverse modalities are emerging. The most used and well-studied approach is to hijack E3 ligases of the ubiquitin–proteasome system. E3 ligases use specific molecular recognition to determine which proteins in the cell are ubiquitinated and degraded. This review focuses on the structural determinants of E3 ligase recruitment of natural substrates and neo-substrates obtained through monovalent molecular glues and bivalent proteolysis-targeting chimeras. We use structures to illustrate the different types of substrate recognition and assess the basis for neo-protein–protein interactions in ternary complex structures. The emerging structural and mechanistic complexity is reflective of the diverse physiological roles of protein ubiquitination. This molecular insight is also guiding the application of structure-based design approaches to the development of new and existing degraders as chemical tools and therapeutics.

中文翻译：

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驱动 E3 连接酶底物特异性进行靶向蛋白质降解：来自自然和实验室的经验教训

利用邻近诱导分子来引导蛋白质靶标降解的方法正在突飞猛进地发展，并且各种模式正在出现。最常用和研究最多的方法是劫持泛素-蛋白酶体系统的 E3 连接酶。 E3 连接酶使用特定的分子识别来确定细胞中的哪些蛋白质被泛素化和降解。本综述重点关注通过单价分子胶和二价蛋白水解靶向嵌合体获得的天然底物和新底物的 E3 连接酶招募的结构决定因素。我们使用结构来说明不同类型的底物识别，并评估三元复杂结构中新蛋白质-蛋白质相互作用的基础。新兴的结构和机制复杂性反映了蛋白质泛素化的不同生理作用。这种分子洞察力还指导基于结构的设计方法的应用，以开发新的和现有的降解剂作为化学工具和治疗方法。