Conformational transition pathway in the activation process of allosteric glucokinase.
Conformational transition pathway in the activation process of allosteric glucokinase.
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DOI：
10.1371/journal.pone.0055857
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Huang M;Lu S;Shi T;Zhao Y;Chen Y;Li X;Liu X;Huang Z;Zhang J
糖酵解酶(GK)是一种糖酵解酶，在调节血糖水平方面发挥着重要作用，因此在治疗年轻2型糖尿病和婴幼儿持续性高胰岛素低血糖方面是一个有潜力的药物靶点。为了研究GK从超开放状态(非活性状态)到闭合状态(活性状态)的激活机制，对该酶进行了一系列常规分子动力学(MD)和靶向分子动力学(TMD)模拟。传统的分子动力学模拟显示，当酶失活时，GK有一个特定的构象系综。7个TMD模拟描述了GK从非活化态到活化态的可靠构象转变路径，并通过分析TMD轨迹的详细结构确定了对GK构象变化重要的组分。结合失活过程，我们的发现表明，GK激活-失活-激活的整个构象途径是一个单向循环，在循环中活跃状态比非活跃状态更不稳定。此外，在激活过程中，葡萄糖在GK的大结构域和连接区的残基的帮助下逐渐调节其结合姿势。此外，用所得的能垒解释了GK对底物的预先存在的平衡和缓慢的结合动力学过程。模拟结果与诱变实验和动力学分析的最新结果一致。我们的观察揭示了变构蛋白中一个复杂的构象过程，从而对变构生物大分子的精细机制有了新的认识，这将有助于靶向变构蛋白的药物设计。
Glucokinase (GK) is a glycolytic enzyme that plays an important role in regulating blood glucose level, thus acting as a potentially attractive target for drug discovery in the treatment of diabetes of the young type 2 and persistent hyperinsulinemic hypoglycemia of infancy. To characterize the activation mechanism of GK from the super-open state (inactive state) to the closed state (active state), a series of conventional molecular dynamics (MD) and targeted MD (TMD) simulations were performed on this enzyme. Conventional MD simulation showed a specific conformational ensemble of GK when the enzyme is inactive. Seven TMD simulations depicted a reliably conformational transition pathway of GK from the inactive state to the active state, and the components important to the conformational change of GK were identified by analyzing the detailed structures of the TMD trajectories. In combination with the inactivation process, our findings showed that the whole conformational pathway for the activation-inactivation-activation of GK is a one-direction circulation, and the active state is less stable than the inactive state in the circulation. Additionally, glucose was demonstrated to gradually modulate its binding pose with the help of residues in the large domain and connecting region of GK during the activation process. Furthermore, the obtained energy barriers were used to explain the preexisting equilibrium and the slow binding kinetic process of the substrate by GK. The simulated results are in accordance with the recent findings from the mutagenesis experiments and kinetic analyses. Our observations reveal a complicated conformational process in the allosteric protein, resulting in new knowledge about the delicate mechanisms for allosteric biological macromolecules that will be useful in drug design for targeting allosteric proteins.
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