人类谷胱甘肽硫转移酶家族等位基因蛋白B与抑制剂作用模型的理论研究

采用分子动力学模拟方法系统地研究了谷胱甘肽硫转移酶家族(Glutathione S-transferases,GSTs)的等位基因蛋白B(GSTP1*B)与抑制剂利尿酸(EA)以及EA的谷胱甘肽(GSH)共轭物EAG(I),EAG(O)的具体结合方式.抑制剂及其谷胱甘肽共轭物与蛋白的相互作用能计算结果及分子动力学轨迹的统计分析结果表明,GSTP1*B与EA的谷胱甘肽共轭物的结合能力优于其与EA的结合能力,Phe8,Arg13,Trp38和Tyr108是作用过程中的关键残基,对稳定抑制剂及其谷胱甘肽共轭物在GSTP1*B的G和H位点的构象具有重要的作用.通过对构象的统计分析发现,残基Phe8和Tyr108与GSTP1*B酶对抑制剂的选择性密切相关.

Theoretical Studies on Interaction Modes Between Human GSTP1*B and Inhibitors

We constructed a high quality model of human GSTP1*B(glutathione S-transferases, Pi class *B variant) and revealed the interactions between protein and three inhibitors including ethacrynic acid(EA) and its conjugate of glutathione EAG(I) and EAG(O)] to explore the structure-function relationship via molecular dynamics(MD) simulations. Based on the results of interaction energy caculation and the analysis of MD simulation trojactory, several critical residues of stablizing the structure of G- and H-site, including Phe8, Arg13, Trp38 and Tyr108, were identified. Our results also show that the conjutation of GSTP1*B protein may increase the binding ability of the inhibitor and the specific selectivity of Phe8 and Tyr108 to the substrate.