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关于皮里丁与铁硫酶IspH结合的洞察力
Ingrid Span1, Ke Wang, Wolfgang Eisenreich
1Center for Integrated Protein Science Munich, Chemistry Department, Technische Universität München , Lichtenbergstrasse 4, 85747 Garching, Germany.
Journal of the American Chemical Society
|May 13, 2014
概括
(E) -1-基-2-甲基-2-乙烯-4-二酸盐还原酶 (IspH) 是一种药物标,对异烯酸生物合成至关重要. 这项研究揭示了二酸盐如何与IspH结合,揭示了抑制铁的独特相互作用.
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:
- 酶 (E) -1-Hydroxy-2-methylbut-2-enyl 4-diphosphate降解酶 (IspH) 含有[Fe4S4]集群,对于细菌和疟疾寄生虫中的异oprenoid生物合成至关重要.
- IspH是重要的药物标,之前已经确定了各种抑制剂,如二酸.
研究的目的:
- 用X射线晶体学阐明二酸与大肠杆菌IspH的结合机制.
- 了解皮里丁二酸盐抑制IspH的结构基础.
主要方法:
- 采用X射线晶体学,确定IspH与四种二酸盐复合物的结构.
- 量子化学计算 (密度函数理论) 用于分析电子结构和结合.
主要成果:
- 在三个晶体结构中,发现[Fe4S4]集群缺少一个铁原子.
- 最强大的抑制剂 (pyridin-3-yl) 甲基二酸盐保持了完整的[Fe4S4]集群,第四个铁原子与酸盐环相互作用.
- 提出了皮里丁和C2碳以及减少的唯一的第四个铁原子之间的侧向 η(2) 协调.
结论:
- 这项研究揭示了一种新的甲基器官相互作用,即二酸酶抑制剂与IspH.的[Fe4S4]集群之间的相互作用.
- 这些发现提供了对IspH抑制的结构性见解,并突出了含有[Fe4S4]的蛋白质的适应性.
- 确定的X射线结构准确地预测了光谱数据,验证了拟议的结合模式.
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