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一个基于结构的设计小分子耗尽hRpn13^Pru和一组精选的KEN盒子蛋白

Xiuxiu Lu¹, Monika Chandravanshi¹, Venkata R Sabbasani²

¹Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.

Nature communications

|March 21, 2024

概括

一种新型化合物,XL44,向蛋白酶子单元hRpn13和相关蛋白质,诱导癌细胞死亡. 这一发现通过利用不同的蛋白质降解途径提供了新的治疗策略.

科学领域:

分子生物学分子生物学
生物化学生物化学
癌症研究癌症研究

背景情况:

蛋白质酶子单元hRpn13在癌细胞中被蛋白质化,产生hRpn13Pru.
DEUBAD域被降解,使得蛋白酶和泛胺结合的Pru域保持完好.

研究的目的:

为了识别和描述hRpn13 Pru的小分子结合剂.
阐明已识别的结合剂的作用机制.
为了研究其在癌症中的治疗潜力.

主要方法:

结构引导的虚拟选以识别hRpn13结合剂.
综合的X射线结晶学和NMR解决了hRpn13 Pru与XL44结合的结构.
TMT-MS (串联质量标记质量谱) 用于识别目标之外的物体.
细胞活力测试和细胞亡测试.

主要成果:

XL44被确定为一个hRpn13绑定剂,其结构被阐明.
在骨髓瘤细胞中,XL44治疗减少了hRpn13Pru.
确定了包括PCLAF和RRM2在内的非目标目标,并由XL44.4消耗.
XL44诱导的hRpn13-依赖的亡和PCLAF-依赖的细胞活力限制.
通过XL44消耗PCLAF需要KEN框,但不需要无处不在.

结论:

XL44诱导了hRpn13Pru的随处可见的损失和KEN盒蛋白的随处可见的独立损失.
XL44表现出限制癌细胞活力的双重机制.
这项研究揭示了一种针对不同蛋白质降解途径的新型治疗策略.

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