Conservation, variability and the modeling of active protein kinases.
Conservation, variability and the modeling of active protein kinases.
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DOI：
10.1371/journal.pone.0000982
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发表时间：
2007-10-03
期刊：
影响因子：
3.7
通讯作者：
Kothary, Rashmi
中科院分区：
文献类型：
--
作者：
Knight, James D. R.;Qian, Bin;Baker, David;Kothary, Rashmi
人类蛋白质组富含蛋白激酶，这种丰富性使得激酶在启动和维持细胞行为方面至关重要。阐明细胞信号网络并操纵其组件以理解和改变行为需要精心设计的抑制剂。这些抑制剂在培养中需要引起和研究网络扰动，并且相同的化合物可以用作治疗疾病的药物。详细了解蛋白激酶的结构生物学，包括它们的共性，差异和底物相互作用模式，对于设计真正用于细胞生物学和疾病治疗的高质量抑制剂是必要的。为此，我们在这里报告所有可用的活性构象蛋白激酶的结构分析，讨论残基保护，这种保护的新功能，独特的性质的非典型激酶和可变性的背景下，底物结合。我们还演示了如何将这些信息用于结构预测。我们的研究结果将不仅用于了解蛋白激酶的功能和进化，但它们突出了激酶药物设计中固有的缺陷，并为实验室和疾病治疗中使用的特定抑制剂的复杂设计提供了适当的策略。
The human proteome is rich with protein kinases, and this richness has made the kinase of crucial importance in initiating and maintaining cell behavior. Elucidating cell signaling networks and manipulating their components to understand and alter behavior require well designed inhibitors. These inhibitors are needed in culture to cause and study network perturbations, and the same compounds can be used as drugs to treat disease. Understanding the structural biology of protein kinases in detail, including their commonalities, differences and modes of substrate interaction, is necessary for designing high quality inhibitors that will be of true use for cell biology and disease therapy. To this end, we here report on a structural analysis of all available active-conformation protein kinases, discussing residue conservation, the novel features of such conservation, unique properties of atypical kinases and variability in the context of substrate binding. We also demonstrate how this information can be used for structure prediction. Our findings will be of use not only in understanding protein kinase function and evolution, but they highlight the flaws inherent in kinase drug design as commonly practiced and dictate an appropriate strategy for the sophisticated design of specific inhibitors for use in the laboratory and disease therapy.
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