影响在位循环添加形成醇抑制剂的固态和动态参数
Yves Bourne1,2, K Barry Sharpless3, Palmer Taylor4
1Aix-Marseille Université, laboratory Architecture et Fonction des Macromolécules Biologiques, Faculté des Sciences de Luminy , 13288 Marseille cedex 09, France.
Journal of the American Chemical Society
|January 6, 2016
概括
乙胆酶 (AChE) 作为现场点击化学反应容器. 在AChE沟内的抑制剂合成显示动态形状变化是有效的三醇形成的关键.
科学领域:
- 生物化学
- 化学生物学
- 结构生物学
背景情况:
- 乙胆酶 (AChE) 具有不同的联结位点:位于沟底部的活性中心和位于沟入口的外围位点.
- 这些站点使ACHE能够作为现场点击化学的微反应器.
- 之前的工作确立了ACHE作为通过循环添加反应合成高亲和度抑制剂的模板.
研究的目的:
- 调查ACHE内部现场点击化学的结构基础.
- 将抑制剂尺寸与反应性相关联,并探索晶体模板中的加速.
- 了解抑制剂合成过程中 AChE 的动态构造变化.
主要方法:
- 用水晶浸泡方法研究ACHE抑制剂复合物.
- 使用X射线结晶学以2.1-2.7 Å的分辨率解决了各种抑制剂和前体的ACHE结构.
- 分析结构数据的重点是AChE峡谷内的侧链运动和形状变化.
主要成果:
- 晶体结构显示合成产物形成与AChE峡谷内的特定侧链重组有关.
- 在与抑制剂结合时观察到His447 (活性部位) 和Tyr341 (口) 的运动.
- 这些运动似乎引导AChE进入有利于合成的短暂状态.
结论:
- 为了促进有利的静电相互作用,AChE在形状之间的动态相互转换至关重要.
- 由于 AChE 的形状灵活性,和亚反应物的适当对齐对于生产性反应是必不可少的.
- 虽然前体结合发生,但电场波动和反应物对齐的合仍然是三醇形成的可能速度限制步骤.
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