预测使用化学蛋白质组学和AlphaFold在二甲基甘激酶上的小分子结合口袋
Roberto Mendez1, Minhaj Shaikh1, Michael C Lemke2
1Department of Chemistry, University of Virginia Charlottesville Virginia 22904 USA ken.hsu@austin.utexas.edu +1 434-297-4864.
RSC chemical biology
|June 9, 2023
概括
糖醇激酶 (DGKs) 是主要的代谢调节剂. 这项研究使用了化学蛋白质组学-AlphaFold方法来绘制DGK结合部位的地图,确定开发向抑制剂的口袋.
科学领域:
- 生物化学 生化学
- 分子生物学分子生物学
- 化学生物学 化学生物学
背景情况:
- 糖醇激酶 (DGKs) 是调节脂质第二信使,糖醇和酸的关键酶.
- 开发DGK的选择性抑制剂对于理解它们的作用和治疗应用至关重要.
- 鉴定细胞环境中小分子结合的可访问的蛋白质口袋对于抑制剂设计至关重要.
研究的目的:
- 通过使用一种新的化学蛋白质组学探针,绘制DGK超级家族的可访问的共价结合点.
- 将化学蛋白质组学数据与AlphaFold结构预测集成,以确定潜在的小分子抑制剂结合口袋.
- 评估域交换对DGK亚型内的探针结合和酶活性的影响.
主要方法:
- 使用了一种硫-三醇探针 (TH211),该探针旨在对DGKs上的氨酸和氨酸残留物进行共聚结合.
- 采用化学保护学-AlphaFold方法,将探头标记与结构建模相结合.
- 构建并分析了具有交换C1调节域 (DGKα和DGKζ) 的DGK嵌合蛋白,以评估该域的功能.
主要成果:
- 在DGK上确定了特定的氨酸和氨酸位点,可通过TH211探针进行共价修饰.
- 将这些可访问的位置映射到DGKs的AlphaFold结构中预测的小分子结合口袋中.
- 观察到DGKα嵌合体中与交换C1域的DGKα嵌合体中TH211探针与催化域口袋结合的损失,与减少的酶活性相关.
结论:
- 该研究提供了DGK家族中可访问的共价准站点的全面地图.
- 化学蛋白质组学和AlphaFold建模的整合成功地预测了小分子结合口袋.
- 这种方法为指导选择性DGK抑制剂的合理设计提供了一个强有力的策略.
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