对双酸盐和法纳西二酸盐合成酶-双酸盐复合物的固态NMR,晶体学和计算研究
Junhong Mao1, Sujoy Mukherjee, Yong Zhang
1Department of Chemistry and Biophysics, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
Journal of the American Chemical Society
|November 9, 2006
概括
双酸盐抑制法二酸盐合成酶 (FPPS),但它们的结合不清楚. 这项研究结合了NMR,量子化学和对接,揭示了双酸盐结合机制,有助于设计新药.
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:
- 双酸盐对于治疗骨疾病至关重要,并显示出作为免疫调节剂和抗感染剂的潜力.
- 它们的机制涉及抑制法纳西二酸盐合成酶 (FPPS),但结合细节仍然难以捉摸.
研究的目的:
- 阐明双酸盐与FPPS的结合机制.
- 为了解酶结合时的侧链和酸脊柱质子化状态提供见解.
- 为了促进新型prenyltransferase抑制剂的合理设计.
主要方法:
- 固态 (13) C, (15) N,和 (31) P 魔术角度样本旋转 (MAS) 的NMR光谱学.
- 量子化学计算 量子化学计算
- 使用NMR衍生电荷的计算对接方法.
- 一个X射线晶体学.
主要成果:
- 获得了有关双酸与FPPS结合时的质子化状态的详细信息.
- 计算对接预测了各种双酸盐与FPPS的结合模式.
- 射线晶体学证实了对两个强效抑制剂的计算预测,显示出很好的一致性.
结论:
- 核磁共振,量子化学和分子对接的综合方法为了解双酸盐-酶相互作用提供了一个强大的策略.
- 这种方法可以加速设计和开发新的先转移酶抑制剂.
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