通过用共价探针进行对比跳跃来扩大可连接蛋白质组
Yuanjin Zhang1, Zhonglin Liu1, Marsha Hirschi2
1Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037 USA.
bioRxiv : the preprint server for biology
|January 31, 2024
概括
研究人员使用化学蛋白质组学来通过修改蛋白质来识别新的药物点. 这种方法有助于发现可以与以前无法向的蛋白质结合的新型化合物.
科学领域:
- 化学生物学是化学生物学.
- 蛋白质组学是指蛋白质组学.
- 药物发现 药物发现
背景情况:
- 超过一半的人类基因具有类似基因,其中一些蛋白质具有独特的反应性半氨酸.
- 化学蛋白质组学识别了对电友敏感的半氨酸,但缺乏半氨酸的类似物中的可结合口袋仍然具有挑战性.
研究的目的:
- 探索使用共价化合物-氨酸相互作用,在缺乏氨酸的类似蛋白质中找到可结合的口袋.
- 开发用于识别环林E1:CDK2复合物的抑制剂的新型试验.
主要方法:
- 基于活动的蛋白质分析 (ABPP) 用于检测修饰蛋白和化学探针之间的反应.
- 纳米BRET-ABPP测试开发用于识别可逆抑制剂.
- X射线晶体学可视化抑制剂结合口袋.
主要成果:
- 改造的CCNE1 (N112C突变体) 特别与烯胺反应,证明了共价结合性.
- 一个新的NanoBRET-ABPP测定确定了CCNE1:CDK2复合物的可逆抑制剂.
- X射线晶体学揭示了CCNE1:CDK2接口上的一个神秘的体口袋.
结论:
- 这项研究提供了一种方法来发现缺乏反应性半氨酸的蛋白质中的可结合口袋.
- 这些发现为利用电恋-氨酸相互作用提供了一份路线图,以扩大药物发现工作.
- 开发的测试可以识别抑制工程和野生类型CCNE1:CDK2复合物的化合物.
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