控制指芯反应性的因素
1Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan.
Journal of the American Chemical Society
|May 18, 2011
概括
指 (Zf) 蛋白核中的键稳定了反应性硫酸盐位点,即使没有直接相互作用. 这一发现有助于识别癌症和逆转录病毒疗法的潜在药物标.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 药用化学 医学化学
背景情况:
- 指 (Zf) 蛋白利用各种协调核中的Zn2+) 离子 (例如,Zn·Cys4).
- 虽然通常是结构性的,但Zf核中的一些Zn结合的硫酸盐表现出反应性,为癌症和逆转录病毒疗法提供药物标.
- 之前的研究表明,S---NH键降低了酸盐的反应性,但没有这些键存在的不反应Zf核.
研究的目的:
- 调查影响指蛋白核中Zn结合的硫酸盐活性的因素.
- 阐明某些富含Cys的部位不活性背后的机制.
- 为药物标识提供区分labile与结构位的指导方针.
主要方法:
- 在指核心中对键相互作用的计算分析.
- 评估直接和间接键对硫酸盐反应性的影响.
- 对于对Zn结合的硫原子的电友性攻击 (例如甲基化) 的自由能量屏障计算.
主要成果:
- 键,无论是从骨干还是第二个Zn离子,都抑制了直接和间接相互作用的Zn结合硫原子的反应性.
- 多个间接的NH---S* 键比直接的NH---S* 键更多地增加了未结合的硫原子甲基化的自由能量屏障.
- 一些已知的非活性Zf核与缺乏H键的Cys配体被解释为这些间接稳定效应.
结论:
- 含有间接的结网,在稳定指蛋白中其他反应性硫酸盐位点方面发挥着至关重要的作用.
- 了解这些稳定机制是区分不稳定与结构位的关键.
- 这项研究为识别治疗干预的新指基药物标提供了洞察力.
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