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Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes.

BTK和cIAP1蛋白降解剂三元复合物的快照和集合。

  • 影响因子:9.33
  • DOI:10.1038/s41589-020-00686-2
  • 作者列表:"Schiemer J","Horst R","Meng Y","Montgomery JI","Xu Y","Feng X","Borzilleri K","Uccello DP","Leverett C","Brown S","Che Y","Brown MF","Hayward MM","Gilbert AM","Noe MC","Calabrese MF
  • 发表时间:2021-02-01
Abstract

:Heterobifunctional chimeric degraders are a class of ligands that recruit target proteins to E3 ubiquitin ligases to drive compound-dependent protein degradation. Advancing from initial chemical tools, protein degraders represent a mechanism of growing interest in drug discovery. Critical to the mechanism of action is the formation of a ternary complex between the target, degrader and E3 ligase to promote ubiquitination and subsequent degradation. However, limited insights into ternary complex structures exist, including a near absence of studies on one of the most widely co-opted E3s, cellular inhibitor of apoptosis 1 (cIAP1). In this work, we use a combination of biochemical, biophysical and structural studies to characterize degrader-mediated ternary complexes of Bruton's tyrosine kinase and cIAP1. Our results reveal new insights from unique ternary complex structures and show that increased ternary complex stability or rigidity need not always correlate with increased degradation efficiency.

摘要

: 异双功能嵌合降解物是一类将靶蛋白募集到E3泛素连接酶以驱动化合物依赖性蛋白降解的配体。从最初的化学工具开始,蛋白质降解物代表了对药物发现越来越感兴趣的机制。对作用机制至关重要的是在靶标、降解物和E3连接酶之间形成三元复合物,以促进泛素化和随后的降解。然而,对三元复杂结构的了解有限,包括对最广泛选择的E3s之一,细胞凋亡抑制剂1 (cIAP1) 的研究几乎缺乏。在这项工作中,我们使用生物化学,生物物理和结构研究的组合来表征布鲁顿酪氨酸激酶和ciap1的降解物介导的三元复合物。我们的研究结果揭示了独特的三元复杂结构的新见解,并表明增加的三元复杂稳定性或刚性并不总是与增加的降解效率相关。

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DOI:10.1007/s11033-021-06299-9
作者列表:["Louvrier A","Terranova L","Meyer C","Meyer F","Euvrard E","Kroemer M","Rolin G"]

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