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目的:探讨抗肿瘤药物新靶点Bcl-2蛋白与底物蛋白的相互作用。方法:以同源模建的方法构建Bcl-2蛋白与底物Bak蛋白的肽片段的复合物的三维结构,并对此结构模型的合理性进行验证。比较复合物结构模型中Bcl-2的活性腔与自由状态结构的差异,分析它与底物肽相互作用的重要位点和残基,并计算它与两类抑制剂的分子对接。结果:构建的Bcl-2复合物结构模型合理,通过比较发现模建的结构模型中活性腔特别是α3前后的部位与自由状态有较大的结构变化,蛋白活性腔侧部的一些酸性碱性极性残基及底部的一些疏水残基对于结合底物蛋白并发挥功能非常关键,这些结果与生物学残基突变实验数据得到了较好的相互验证。结论:本研究构建了合理的Bcl-2蛋白与底物Bak蛋白肽片段的复合物的三维结构。
Objective: To explore the interaction between Bcl-2 protein and substrate protein as a new target of anticancer drug. METHODS: The three-dimensional structure of the complex of Bcl-2 protein and peptide fragment of Bak protein was constructed by homology modeling. The rationality of this structural model was also validated. The differences between the active cavity and the free state structure of Bcl-2 in the composite structure model were compared, and the important sites and residues of its interaction with the substrate peptide were analyzed. Results: The structural model of Bcl-2 complex was reasonable. Compared with the free state, the structure of Bcl-2 complex was more structurally modified. The acidic basicity Polar residues and some hydrophobic residues at the bottom are critical for the binding of substrate proteins and their function. These results are in good agreement with experimental data on the mutation of biological residues. Conclusion: This study constructed a reasonable three-dimensional structure of the Bcl-2 protein complex with the substrate Bak protein peptide fragment.