物理化学学报 >> 2011, Vol. 27 >> Issue (01): 207-212.doi: 10.3866/PKU.WHXB20110116

生物物理化学 上一篇    下一篇

分子动力学模拟研究结构金属镁离子在GSK-3β激酶磷酸化中的作用

孙浩1, 蒋勇军2, 俞庆森3, 高慧3   

  1. 1. 西南林业大学, 昆明 650224;
    2. 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, 浙江宁波315100;
    3. 浙江大学化学系, 杭州 310027
  • 收稿日期:2010-09-01 修回日期:2010-10-15 发布日期:2010-12-31
  • 通讯作者: 蒋勇军 E-mail:yjjiang@nit.zju.edu.cn
  • 基金资助:

    国家高技术研究发展计划(863)(2007AA02Z301), 国家自然科学基金(20803063), 宁波市自然科学基金(2010A610024)及西南林业大学重点科研基金(110932)资助项目

Molecular Dynamics Simulations on the Role of Structural Mg2+ Ions in Phosphoryl Transfer Catalyzed by GSK-3β

SUN Hao1, JIANG Yong-Jun2, YU Qing-Sen3, GAO Hui3   

  1. 1. Southwest Forestry University, Kunming 650224, P. R. China;
    2. Key Laboratory for Molecular Design and Nutrition Engineering of Ningbo City, Ningbo Institute of Technology, Zhejiang University, Ningbo 315100, Zhejiang Province, P. R. China;
    3. Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
  • Received:2010-09-01 Revised:2010-10-15 Published:2010-12-31
  • Contact: JIANG Yong-Jun E-mail:yjjiang@nit.zju.edu.cn
  • Supported by:

    The project was supported by the National High Technology Research and Development Program of China (863) (2007AA02Z301), National Natural Science Foundation of China (20803063), Natural Science Foundation of Ningbo, China (2010A610024), and Key Scientific Research Foundation of Southwest Forestry University, China (110932).

摘要:

糖原合成酶激酶-3β(GSK-3β)是一种丝氨酸/苏氨酸蛋白激酶, 调节糖原合成酶的活性, 并在生物体内的多条信号通路中发挥作用. GSK-3β是糖尿病, 肿瘤, 急性炎症, 早老性痴呆等多种复杂疾病的药物作用靶标.Mg2+是GSK-3β激酶的保守结构金属离子, 与三磷酸腺苷(ATP)分子作用, 在激酶的磷酸化中扮演重要的角色,本文阐明了两个Mg2+离子(Mg2+I , Mg2+II)在激酶磷酸化中的作用: Mg2+稳定GSK-3β与ATP的构象. 缺乏Mg2+离子, GSK-3β结构的柔性增强, 同时ATP的构象发生改变, 相对Mg2+II离子而言, Mg2+I离子在磷酸化反应中的作用更突出, 但Mg2+II离子也是必不可少的, 如果没有Mg2+II离子, Lys183 无法独立稳定ATP的合适构象. 当两个Mg2+离子都不存在时, ATP形成分子内的氢键, 成为一种折叠的构象.

关键词: GSK-3β激酶, 磷酸化, Mg2+, 结构金属离子, 分子动力学模拟

Abstract:

Glycogen synthase kinase-3β(GSK-3β) is a kind of serine/threonine protein kinase. It regulates the synthesis of glycogen and plays an important part in several signal pathways. It is believed to be an important target for a number of diseases such as diabetes, cancers, chronic inflammation, and Alzheimer's disease. Mg2+ ions are conserved structural metal ions in GSK-3β and they interact with adenosine-triphosphate (ATP). They are very important in phosphoryl transfer in the kinase. In this paper, the effect of two Mg2+ ions (Mg2+I, Mg2+II) on GSK-3β is illustrated. Mg2+ can stabilize the conformation of GSK-3β and ATP. Without Mg2+, the stabilization of GSK-3β reduces explicitly and the conformation of ATP changes. Mg2+I is important in the phosphorylation reaction while Mg2+II is essential and Lys183 alone cannot maintain the conformation of ATP without the assistance of Mg2+II . ATP forms intramolecular hydrogen bonds and adopts a folded conformation when both Mg2+I and Mg2+II are absent.

Key words: GSK-3β kinase, Phosphoryl transfer, Mg2+, Structural metal ion, Molecular dynamics simulation

MSC2000: 

  • O641