Lindvall M K, Pihko P M, Koskinen A M
Department of Chemistry, University of Oulu, Linnanmaa, FIN-90570 Oulu, Finland.
J Biol Chem. 1997 Sep 12;272(37):23312-6. doi: 10.1074/jbc.272.37.23312.
The catalytic subunits of serine/threonine protein phosphatases 1 and 2A are subject to inhibition by various toxins such as the microcystins, the nodularins, okadaic acid, tautomycin, and the calyculins. A recent paper (Bagu, J. R., Sykes, B. D, Craig, M. M., and Holmes, C. F. B. (1997) J. Biol. Chem. 272, 5087-5097) reported the successful docking of the crystal structure of calyculin A to the crystal structure of protein phosphatase-1. Unfortunately, the model presented there is based on the structure of the unnatural enantiomer of calyculin A and must therefore be incorrect. We have developed a spiroketal vector model which appears to account for the spatial orientation of the hydrophobic and basic chains extending from the spiroketal-phosphate core of calyculin A. The model also clearly demonstrates why the unnatural enantiomer of calyculin A does not fit properly into the pocket of the active site. Based on our model, we present a possible open binding mode for calyculin A in the enzyme. This open structure is conceptually similar to the predicted binding mode of the peptide inhibitor DARPP-32 to the enzyme; the hydrophobic, metal-binding, and electrostatic interactions are all retained in this model.
丝氨酸/苏氨酸蛋白磷酸酶1和2A的催化亚基会受到多种毒素的抑制，如微囊藻毒素、节球藻毒素、冈田酸、互隔交链孢酚单甲醚和花萼海绵诱癌素。最近一篇论文（Bagu, J. R., Sykes, B. D, Craig, M. M., and Holmes, C. F. B. (1997) J. Biol. Chem. 272, 5087 - 5097）报道了花萼海绵诱癌素A的晶体结构与蛋白磷酸酶-1的晶体结构成功对接。不幸的是，文中给出的模型基于花萼海绵诱癌素A非天然对映体的结构，因此必然是不正确的。我们构建了一个螺环缩酮载体模型，该模型似乎能够解释从花萼海绵诱癌素A的螺环缩酮 - 磷酸核心延伸出的疏水链和碱性链的空间取向。该模型还清楚地说明了为什么花萼海绵诱癌素A的非天然对映体不能正确地适配到活性位点的口袋中。基于我们的模型，我们提出了花萼海绵诱癌素A在该酶中可能的开放结合模式。这种开放结构在概念上类似于肽抑制剂DARPP - 32与该酶预测的结合模式；在这个模型中，疏水、金属结合和静电相互作用都得以保留。
