Bertini I, Calderone V, Fragai M, Luchinat C, Talluri E
Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy.
J Med Chem. 2009 Aug 13;52(15):4838-43. doi: 10.1021/jm900610k.
The inhibition of a subgroup of human serine/threonine protein phosphatases is responsible for the cytotoxicity of cantharidin and norcantharidin against tumor cells. It is shown that the anhydride rings of cantharidin and norcantharidin are hydrolyzed when bound to the catalytic domain of the human serine/threonine protein phosphatases 5 (PP5c), and the high-resolution crystal structures of PP5c complexed with the corresponding dicarboxylic acid derivatives of the two molecules are reported. Norcantharidin shows a unique binding conformation with the catalytically active Mn2PP5c, while cantharidin is characterized by a double conformation in its binding mode to the protein. Different binding modes of norcantharidin are observed depending of whether the starting ligand is in the anhydride or in the dicarboxylic acid form. All these structures will provide the basis for the rational design of new cantharidin-based drugs.
人丝氨酸/苏氨酸蛋白磷酸酶亚组的抑制作用是斑蝥素和去甲斑蝥素对肿瘤细胞产生细胞毒性的原因。研究表明，斑蝥素和去甲斑蝥素的酸酐环在与人丝氨酸/苏氨酸蛋白磷酸酶5（PP5c）的催化结构域结合时会发生水解，并报道了PP5c与这两种分子相应二羧酸衍生物复合的高分辨率晶体结构。去甲斑蝥素与具有催化活性的Mn2PP5c呈现独特的结合构象，而斑蝥素在与该蛋白的结合模式上具有双重构象。根据起始配体是酸酐形式还是二羧酸形式，观察到去甲斑蝥素不同的结合模式。所有这些结构将为基于斑蝥素的新型药物的合理设计提供依据。
