氨基甲基化物通过形成扩展的分子内键网络锁定在表面的素上
Jacqueline Weaver1, Gregory B Craven2, Linh Tram1
1Chemistry and Chemical Biology Program, University of California─San Francisco, San Francisco, California 94143, United States.
Journal of the American Chemical Society
|August 23, 2024
概括
研究人员开发了新的甲基连接物,有效地向Hsp90的表面暴露的氨酸残留物. 这些配体形成稳定的胺基,为蛋白质修饰和药物开发提供了新的策略.
科学领域:
- 生物化学
- 化学生物学
- 结构生物学
背景情况:
- 开发用于特定氨酸修饰的电友性配体具有挑战性.
- 甲抑制剂通常向蛋白质激酶中的埋藏 lysine 残留物.
- 在暴露于溶剂的lysine位点上,salicylaldimine的稳定性是不确定的.
研究的目的:
- 研究基于甲的抑制剂对表面暴露的氨酸残留物的疗效.
- 开发针对热冲击蛋白90 (Hsp90) 的ATPase域的新型配体.
- 探索制造耐水解胺的策略.
主要方法:
- 氨基甲基替代盐酸的合成
- 用Hsp90测定配体结合和停留时间.
- 结晶学分析连接蛋白质复合体.
主要成果:
- 鉴定出具有较长停留时间的甲基连体,向Hsp90上的表面素.
- 实现了Hsp90与化合物的几乎不可逆转的接触.
- 通过分子内键阐明了 imine 稳定性的结构基础.
结论:
- 氨基甲基甲酸可在暴露于溶剂的 lysine 残留物中形成形状稳定,耐水解的 imines.
- 这种策略即使素远离配体结合部位也是有效的.
- 为开发向蛋白调节剂提供了一个潜在的平台.
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