结构研究本质上有障碍的MLL融合蛋白AF9与二胺抑制剂复合
Yuting Yang1, Ejaz Ahmad1, Vidhya Premkumar1
1Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
概括
研究人员设计了一种融合蛋白来结晶AF9内在无序的域,揭示了抑制剂的高分辨率结构. 这一突破有助于开发针对AF9和ENL的新型癌症药物.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 癌症研究 癌症研究
背景情况:
- AF9 (MLLT3) 和ENL (MLLT1) 是YEATS家族蛋白质,对于转录调节和MLL重排列白血病至关重要.
- 这些蛋白质形成融合蛋白,招募DOT1L,通过异常基因表达驱动白血病发生.
- AF9 ANC1同质域 (AHD) 本质上是无序的,并介导DOT1L相互作用,在结合时经历折叠.
研究的目的:
- 开发一种蛋白质工程策略,用于对本质上有障碍的AF9 AHD域进行结构性研究.
- 为了获得AF9 AHD的高分辨率晶体结构,与二胺抑制剂复合.
- 为了获得对蛋白质抑制剂相互作用的洞察力,用于开发新型治疗剂.
主要方法:
- 使用的马尔托结合蛋白 (MBP) 作为结晶伴侣,通过链接器与AF9 AHD域融合.
- 嵌入二硫化物键,以促进衍射质量的晶体的形成.
- 确定MBP-AF9 AHD融合蛋白质的结晶结构,与2.1-2.6 Å分辨率的皮相聚抑制剂复合.
主要成果:
- 成功设计并结晶了二硫化物桥接的MBP-AF9 AHD融合蛋白与二胺抑制剂.
- 获得了第一系列AF9 AHD及其抑制剂的高分辨率晶体复合结构.
- 观察到与AF9 AHD/DOT1L NMR结构的结构相似性,在由键稳定的β-hairpin区域有特定的差异.
结论:
- 蛋白质工程策略使其能够对内在无序的AF9 AHD域进行结构性表征.
- 确定的结构为AF9 AHD/抑制剂相互作用提供了关键的见解.
- 这些发现将有助于开发针对AF9/ENL AHD域的新型抑制剂,用于治疗目的.
关键词:
AF9 AF9 AF9 AF9 AF9 AF9 AF9 AF9 AF9 AF9DOT1LL 在线播放在 MBP 融合过程中,MBP 融合在X射线晶体学.双硫化物桥梁是什么意思本质上是无序的蛋白质.类模仿药物是什么?更多相关视频
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