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化学学报
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化学学报 ›› 2009, Vol. 67 ›› Issue (13): 1461-1468. 上一篇    下一篇

研究论文

抑制剂BD2对PKA与PKC βII的抑制选择性研究

金海晓a 吴天星*,b 严小军a 蒋勇军c 邹建卫c

  

  1. (a宁波大学海洋生物工程重点实验室 宁波 315211)
    (b浙江大学化学系 杭州 310027)
    (c浙江大学宁波理工学院分子设计与营养工程市重点实验室 宁波 315100)

  • 投稿日期:2008-07-08 修回日期:2008-12-15 发布日期:2009-07-14
  • 通讯作者: 吴天星

Study on Selectivity of Inhibitor BD2 for PKA over PKC βII

Jin, Haixiao a Wu, Tianxing *,b Yan, Xiaojun a Jiang, Yongjun c Zou, Jianwei c   

  1. (a Key Laboratory of Marine Biotechnology, Ningbo University, Ningbo 315211)
    (b Department of Chemistry, Zhejiang University, Hangzhou 310027)
    (c Key Laboratory for Molecular Design and Nutrition Engineering, Ningbo Institute of Technology,
    Zhejiang University, Ningbo 315100)
  • Received:2008-07-08 Revised:2008-12-15 Published:2009-07-14
  • Contact: Wu, Tianxing

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蛋白激酶A (PKA)和蛋白激酶C (PKC)的过度表达导致细胞生长分化异常, 是治疗肿瘤的潜在靶点. 抑制剂BD2对PKA和PKC抑制作用存在高选择性. 为了探讨BD2高选择性机制, 本工作以PKA与BD2复合物的晶体结构为模板, 通过同源模建结合分子对接的方法构建PKC βII与BD2复合物的结构, 并对PKA-BD2复合物和PKC-BD2复合物进行了2.5 ns的分子动力学模拟, 运用MM-GBSA方法计算了结合自由能, 通过能量分解的方法考察PKA和PKC的主要残基与BD2之间的相互作用和识别机制. 结合能分析结果很好地描述了BD2对PKA抑制活性比其对PKC抑制活性高这一实验现象. 氢键分析和能量分解结果共同说明了BD2的B环和酰胺链部分与PKA和PKC中相应位点的残基之间的相互作用存在差异, 这是BD2存在选择性的内在因素. BD2高选择性作用机制的阐明为进一步基于结构的balanol类抑制剂的结构设计和优化提供了合理的指导.

关键词: 蛋白激酶A (PKA), 蛋白激酶C (PKC), 同源模建, 分子对接, 分子动力学模拟, 抑制选择性

Protein kinase A (PKA) and protein kinase C (PKC) are potential targets in treating tumour and their over expression leads to cellular proliferation and differentiation abnormally. BD2 is a high selective inhibitor for PKA over PKC. In order to elucidate the mechanism of the high selectivity of BD2, in this paper, using the crystal structure of PKA complexed with BD2 as the template, model of PKC βII was built by homology modeling and its complex with BD2 was constructed by molecular docking. 2.5 ns molecular dynamics simulations were carried out on PKA-BD2 complex and PKC-BD2 complex. The binding energy of BD2 with PKA and PKC was calculated by MM-GBSA method, and the interaction between BD2 with the key residues of the two protein kinases was evaluated by energy decomposition analysis. The result of binding energy can described the experimental phenomenon that BD2 is high selective inhibitor for PKA over PKC. The difference of the interaction of B ring and acidamide of BD2 with PKA and PKC was evaluated by hydrogen bond analysis and energy decomposition analysis, which is intrinsic factor for selectivity of BD2. The mechanism of the high selectivity of BD2 was elucidated, which provides the basis for designing and optimizing balanol analogue inhibitor.

Key words: protein kinase A (PKA), protein kinase C (PKC), homology modeling, molecular docking, molecular dynamics simulation, inhibition selectivity