Heterobifunctional small-molecule degraders that induce protein degradation through ligase-mediated ubiquitination have shown considerable promise as a new pharmacological modality. However, we currently lack a detailed understanding of the molecular basis for target recruitment and selectivity, which is critically required to enable rational design of degraders. Here we utilize a comprehensive characterization of the ligand-dependent CRBN-BRD4 interaction to demonstrate that binding between proteins that have not evolved to interact is plastic. Multiple X-ray crystal structures show that plasticity results in several distinct low-energy binding conformations that are selectively bound by ligands. We demonstrate that computational protein-protein docking can reveal the underlying interprotein contacts and inform the design of a BRD4 selective degrader that can discriminate between highly homologous BET bromodomains. Our findings that plastic interprotein contacts confer selectivity for ligand-induced protein dimerization provide a conceptual framework for the development of heterobifunctional ligands.

中文翻译：

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结合中的可塑性赋予配体诱导的蛋白质降解选择性。

通过连接酶介导的泛素化诱导蛋白质降解的异双功能小分子降解剂作为一种新的药理方法已显示出可观的前景。但是，我们目前对靶标募集和选择性的分子基础缺乏详细的了解，而这对于合理设计降解子至关重要。在这里，我们利用依赖配体的CRBN-BRD4相互作用的全面表征来证明尚未进化为相互作用的蛋白质之间的结合是可塑性的。多个X射线晶体结构表明，可塑性导致几种不同的低能结合构象，这些构象被配体选择性地结合。我们证明计算的蛋白质-蛋白质对接可以揭示潜在的蛋白质间接触，并告知BRD4选择性降解物的设计，可以区分高度同源的BET溴结构域。我们的发现，塑料间蛋白接触赋予配体诱导的蛋白二聚化选择性，为异双功能配体的发展提供了概念框架。