Tyndall Joel D A, Lue Hongqi, Rutledge Malcolm T, Bernhagen Jurgen, Hampton Mark B, Wilbanks Sigurd M
School of Pharmacy, University of Otago, PO Box 56, Dunedin 9054, New Zealand.
Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012 Sep 1;68(Pt 9):999-1002. doi: 10.1107/S1744309112030552. Epub 2012 Aug 29.
Macrophage migration inhibitory factor is irreversibly inhibited via covalent modification by phenethyl isothiocyanate, a naturally occurring compound with anti-inflammatory and anticancer properties. The structure of the modified protein obtained from X-ray diffraction data to 1.64 Å resolution is presented. The inhibitor sits within a deep hydrophobic pocket between subunits of the homotrimer and is highly ordered. The secondary structure of macrophage migratory inhibitory factor is unchanged by this modification, but there are significant rearrangements, including of the side-chain position of Tyr37 and the main chain of residues 31-34. These changes may explain the decreased binding of the modified protein to the receptor CD74. Together with the pocket, the areas of conformational change define specific targets for the design of more selective and potent inhibitors as potential therapeutics.
巨噬细胞移动抑制因子通过异硫氰酸苯乙酯的共价修饰被不可逆地抑制，异硫氰酸苯乙酯是一种具有抗炎和抗癌特性的天然化合物。本文给出了从分辨率为1.64 Å的X射线衍射数据获得的修饰后蛋白质的结构。抑制剂位于同三聚体亚基之间的一个深疏水口袋内，且高度有序。这种修饰并未改变巨噬细胞移动抑制因子的二级结构，但存在显著的重排，包括Tyr37侧链位置和31 - 34位残基的主链。这些变化可能解释了修饰后蛋白质与受体CD74结合能力的下降。与该口袋一起，构象变化区域为设计更具选择性和强效的抑制剂作为潜在治疗药物定义了特定靶点。
