Information Technology Laboratory, National Institute of Standards and Technology, Gaithersburg, MD 20899, USA.
J Mol Biol. 2010 Aug 20;401(3):478-92. doi: 10.1016/j.jmb.2010.06.040. Epub 2010 Jun 25.
The crystal structure of the cdk5/p25 complex has provided information on possible molecular mechanisms of the ligand binding, specificity, and regulation of the kinase. Comparative molecular dynamics simulations are reported here for physiological conditions. This study provides new insight on the mechanisms that modulate such processes, which may be exploited to control pathological activation by p25. The structural changes observed in the kinase are stabilized by a network of interactions involving highly conserved residues within the cyclin-dependent kinase (cdk) family. Collective motions of the proteins (cdk5, p25, and CIP) and their complexes are identified by principal component analysis, revealing two conformational states of the activation loop upon p25 complexation, which are absent in the uncomplexed kinase and not apparent from the crystal. Simulations of the uncomplexed inhibitor CIP show structural rearrangements and increased flexibility of the interfacial loop containing the critical residue E240, which becomes fully hydrated and available for interactions with one of several positively charged residues in the kinase. These changes provide a rationale for the observed high affinity and enhanced inhibitory action of CIP when compared to either p25 or the physiological activators of cdk5.
该 cdk5/p25 复合物的晶体结构提供了关于配体结合、特异性和激酶调节的可能分子机制的信息。这里报告了生理条件下的比较分子动力学模拟。这项研究为调节这些过程的机制提供了新的见解，这些机制可能被用来控制 p25 的病理性激活。在激酶中观察到的结构变化通过涉及细胞周期蛋白依赖性激酶（cdk）家族内高度保守残基的相互作用网络得到稳定。通过主成分分析鉴定了蛋白质（cdk5、p25 和 CIP）及其复合物的集体运动，揭示了 p25 复合物化后激活环的两种构象状态，在未复合的激酶中不存在，也不是晶体中明显的。未复合抑制剂 CIP 的模拟显示结构重排和包含关键残基 E240 的界面环的柔韧性增加，该残基完全水合并可与激酶中的几个正电荷残基之一相互作用。这些变化为 CIP 与 p25 或 cdk5 的生理激活剂相比表现出的高亲和力和增强的抑制作用提供了合理的解释。
