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(英文)

Molecular Dynamics Simulations on the Role of Structural Mg^(2+) Ions in Phosphoryl Transfer Catalyzed by GSK-3β

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(Mg2I+,Mg2II+)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Mg2II+离子而言,Mg2I+离子在磷酸化反应中的作用更突出,但Mg2II+离子也是必不可少的,如果没有Mg2II+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.

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.