Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Nat Chem Biol. 2018 Jul;14(7):706-714. doi: 10.1038/s41589-018-0055-y. Epub 2018 Jun 11.
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.
通过连接酶介导的泛素化诱导蛋白质降解的杂双功能小分子降解剂作为一种新的药理学模式显示出了巨大的潜力。然而，我们目前还缺乏对靶标招募和选择性的分子基础的详细了解，这对于合理设计降解剂是至关重要的。在这里，我们利用对配体依赖性 CRBN-BRD4 相互作用的全面表征，证明了没有进化到相互作用的蛋白质之间的结合具有可塑性。多个 X 射线晶体结构表明，这种可塑性导致了几个不同的低能量结合构象，这些构象被配体选择性地结合。我们证明，计算蛋白质-蛋白质对接可以揭示潜在的蛋白质间接触，并为设计可以区分高度同源的 BET 溴结构域的 BRD4 选择性降解剂提供信息。我们的发现表明，蛋白质间的可塑性接触赋予了配体诱导的蛋白质二聚化的选择性，为杂双功能配体的开发提供了一个概念框架。
