Structural interactions dictate the kinetics of macrophage migration inhibitory factor inhibition by different cancer-preventive isothiocyanates.
Structural interactions dictate the kinetics of macrophage migration inhibitory factor inhibition by different cancer-preventive isothiocyanates.
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DOI：
10.1021/bi3005494
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发表时间：
2012-09-25
期刊：
影响因子：
2.9
通讯作者：
Lolis EJ
中科院分区：
文献类型：
--
作者：
Crichlow GV;Fan C;Keeler C;Hodsdon M;Lolis EJ
膳食营养素对细胞过程的调节已知会影响癌症发展的可能性。一类预防癌症的营养素，异硫氰酸酯（ITCs），从食用十字花科蔬菜中提取，已知对细胞生物化学有各种影响。ITCs的一个靶点是巨噬细胞迁移抑制因子（MIF），这是一种广泛表达的蛋白，已知具有炎症、促肿瘤、促血管生成和抗凋亡特性。MIF被多种ITCs共价抑制，这在一定程度上解释了它们如何发挥预防癌症的作用。我们报道了人类MIF与苯乙基异硫氰酸酯和l -萝卜硫素（分别来自豆瓣菜和西兰花的膳食异硫氰酸酯）结合的晶体结构，并将这两种异硫氰酸酯的结构特征与MIF失活的二级速率常数联系起来。我们还利用这些配合物的核磁共振HSQC谱来表征MIF结构的变化，并观察到亚基界面的许多变化。虽然许多化学变化没有改变，但对于这两种异硫氰酸酯来说，许多变化在大小或方向上都没有相似的特征。这两种ITCs结合模式的差异提供了一种利用结构-活性关系来揭示MIF生物相互作用的方法。这项研究的结果为开发针对MIF的治疗方法提供了一个框架。
Regulation of cellular processes by dietary nutrients is known to affect the likelihood of cancer development. One class of cancer preventive nutrients, isothiocyanates (ITCs) derived from consumption of cruciferous vegetables, is known to have various effects on cellular biochemistry. One target of ITCs is macrophage migration inhibitory factor (MIF), a widely expressed protein with known inflammatory, pro-tumorigenic, pro-angiogenic, and anti-apoptotic properties. MIF is covalently inhibited by a variety of ITCs, which in part, may explain how they exert their cancer-preventive effects. We report the crystallographic structures of human MIF bound to phenethylisothiocyanate and to L-sulforaphane (dietary isothiocyanates derived from watercress and broccoli, respectively), and correlate structural features of these two isothiocyanates with their second-order rate constants for MIF inactivation. We also characterize changes in the MIF structure using NMR HSQC spectra of these complexes and observe many changes at the subunit interface. While a number of chemical shifts do not change, many of those that change do not have similar features in magnitude or direction for the two isothiocyanates. The difference in the binding modes of these two ITCs provides a means of using structure-activity relationships to reveal insights into MIF biological interactions. The results of this study provide a framework for the development of therapeutics that target MIF.
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DOI：
10.1042/bj20091170
发表时间：
2009-10-12
期刊：
The Biochemical journal
影响因子：
--
作者：
Cross JV;Rady JM;Foss FW;Lyons CE;Macdonald TL;Templeton DJ
通讯作者：
Templeton DJ
影响因子：
4.8
作者：
Cho, Yoonsang;Jones, Brian F.;Cappello, Michael
通讯作者：
Cappello, Michael
影响因子：
30.5
作者：
de Jong, YP;Abadia-Molina, AC;Terhorst, C
通讯作者：
Terhorst, C
影响因子：
2.7
作者：
Jorgensen, William L.;Gandavadi, Sunilkumar;Bucala, Richard
通讯作者：
Bucala, Richard
影响因子：
5.7
作者：
Okazaki, K;Umemura, T;Hirose, M
通讯作者：
Hirose, M