循环类可以向PHD指阅读器域的芳香,以调节表观遗传蛋白质功能
Oliver D Coleman1,2,3, Jessica Macdonald2, Ben Thomson2
1School of Natural and Environmental Sciences - Chemistry, Newcastle University Newcastle NE1 7RU UK akane.kawamura@ncl.ac.uk.
Chemical science
|July 7, 2023
概括
研究人员开发了一种新型循环抑制剂OC9,以向KDM7基因组脱甲基酶中的植物主体 (PHD) 指. 这种抑制剂为表观遗传药物发现和理解蛋白质相互作用提供了新的策略.
科学领域:
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 化学生物学 化学生物学
- 结构生物学 结构生物学
背景情况:
- 植物主体 (PHD) - - 指是重要的表观遗传阅读器,能够识别组织蛋白修饰.
- PHD指的失调与各种人类疾病有关.
- 用化学抑制剂准PHD指仍然是一个重大挑战.
研究的目的:
- 开发一种针对KDM7基因组脱甲基酶的PHD指的强效和选择性抑制剂.
- 探索一种用于PHD指抑制的新型非氨酸识别动机.
- 为了研究KDM7脱甲基酶活性的全调节.
主要方法:
- 用于循环库构建的mRNA显示器.
- 生物化学测试以评估抑制剂的强度和选择性.
- 化学蛋白质组分析用于细胞中的向参与.
主要成果:
- 一种新的循环抑制剂 (OC9) 被开发出来,针对KDM7基因组脱甲基酶.
- OC9通过一种新的氨酸介导相互作用中断H3K4me3结合,绕过了阴离子-π相互作用.
- OC9选择调节KDM7A和KDM7B脱甲基酶活性,并在T细胞淋巴瘤细胞中激活KDM7.
结论:
- mRNA显示是有效的产生抑制剂对具有挑战性的表观遗传读者蛋白质.
- OC9代表了用于PHD指生物和表观遗传调节的新化学探针.
- 这些发现为脱甲基酶活性的全调节和药物开发开辟了道路.
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