通过使用应变激活的环烯电发现全蛋白质连接体和标
Yue Liu1,2,3, Zhongtang Yu1,2,3, Peishan Li1,2,3
1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
Journal of the American Chemical Society
|July 17, 2024
概括
研究人员为化学生物学开发了基于环的新型电友. 这些探测器在乳酸脱酶A (LDHA) 和粘附调节分子1 (ADRM1) 等蛋白质中发现了新的氨酸标,有助于药物发现.
科学领域:
- 化学生物学
- 医学化学
- 蛋白质组学
背景情况:
- 共价联体是重要的化学探针和治疗剂.
- 需要扩大氨酸反应电的范围以进行先进的蛋白质组定型.
- 基于环的电友为化学探测器开发提供了新的途径.
研究的目的:
- 开发一种基于环烯的新型应变电友.
- 扩大氨酸反应电友的资料,用于蛋白质组的分析.
- 识别和验证新的可结合的氨酸残留物及其功能影响.
主要方法:
- 开发基于环的抗压电友.
- 使用新型电友的蛋白质组概况.
- 基于碎片的连接物发现 (FBLD) 来识别反应碎片.
- 生物化学测试以确认共价结合和功能影响.
主要成果:
- 在乳酸脱酶A (LDHA) 中识别C163和在粘附调节分子1 (ADRM1) 中识别C88作为可结合的残留物.
- 发现Y-35片段对含有硫素域蛋白12 (TXD12) 的C66具有强烈的反应性.
- 证明Y-35对TXD12的共价结合会影响下游信号,导致抗生存和抗增殖效应.
- 验证二碳烯-环作为用于开发针对GSTO1的双共价抑制剂的电友弹头.
结论:
- 基于环的新型电友扩大了对氨酸反应探针的开发工具.
- 在LDHA和ADRM1中发现的可结合的残留物为调节蛋白功能提供了新的点.
- TXD12及其与Y-35的相互作用突出显示出一种新的抗癌途径.
- 在克服耐药性方面,二碳烯基基抑制剂显示出有前途.
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