神经元氧化合成酶的血液协调抑制剂. 铁-硫乙烯协调通过疏水接触稳定,而无需增加抑制剂的功效
Jeffrey D Martell1, Huiying Li, Tzanko Doukov
1Department of Chemistry, Center for Molecular Innovation and Drug Discovery, and Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois 60208-3113, USA.
Journal of the American Chemical Society
|December 18, 2009
概括
这项研究介绍了与结合的乙烯抑制剂的第一个晶体结构,揭示了对神经元氧化合成酶 (nNOS) 抑制的见解. 硫乙烯-海姆相互作用比预期的弱,结合受到海姆铁的影响.
科学领域:
- 生物化学 生物化学
- 药用化学 医学化学
- 结构生物学 结构生物学
背景情况:
- 血红素-硫乙烯相互作用是常见的与甲氨酸连接体.
- 基于铁的血协调 (II型) 抑制剂由于Fe-S键的不稳定性而罕见.
研究的目的:
- 设计和表征一种基于铁的新型神经氧化物合成酶 (nNOS) 抑制剂.
- 在nNOS中阐明乙烯-协调的结构基础.
主要方法:
- 用光谱光度和X射线晶体学来描述抑制剂结合.
- 一系列的乙烯化合物 (3-8) 被合成和评估.
主要成果:
- 获得了第一个结合铁 (nNOS) 的乙烯抑制剂的晶体结构.
- 化合物4-8表现出铁性nNOS的I型抑制,在降解为铁性nNOS时切换到II型.
- 与预期相反,铁-血结合并没有增强抑制剂的功效.
结论:
- 这项研究提供了第一个结构证据,证明任何酶中都存在乙烯-协调.
- 铁-结合的强度比以前假设的要弱,特别是铁.
- 疏水性相互作用对于稳定乙烯-协调至关重要,微妙的结构变化显著影响结合形状.
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