Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, D-44227 Dortmund, Germany.
Arch Pharm (Weinheim). 2010 Apr;343(4):193-206. doi: 10.1002/ardp.201000028.
The 512 protein kinases encoded by the human genome are a prime example of nature's ability to create diversity by introducing variations to a highly conserved theme. The activity of each kinase domain is controlled by layers of regulatory mechanisms involving different combinations of post-translational modifications, intramolecular contacts, and intermolecular interactions. Ultimately, they all achieve their effect by favoring particular conformations that promote or prevent the kinase domain from catalyzing protein phosphorylation. The central role of kinases in various diseases has encouraged extensive investigations of their biological function and three-dimensional structures, yielding a more detailed understanding of the mechanisms that regulate protein kinase activity by conformational changes. In the present review, we discuss these regulatory mechanisms and show how conformational changes can be exploited for the design of specific inhibitors that lock protein kinases in inactive conformations. In addition, we highlight recent developments to monitor ligand-induced structural changes in protein kinases and for screening and identifying inhibitors that stabilize enzymatically incompetent kinase conformations.
人类基因组编码的 512 种蛋白激酶是大自然通过对高度保守的主题进行变异创造多样性的一个主要范例。每个激酶结构域的活性都受到多层次的调节机制的控制，这些机制涉及不同组合的翻译后修饰、分子内接触和分子间相互作用。最终，它们都通过促进或阻止激酶结构域催化蛋白质磷酸化来实现其效果，从而达到特定的构象。激酶在各种疾病中的核心作用促使人们对其生物学功能和三维结构进行了广泛的研究，从而更深入地了解了通过构象变化调节蛋白激酶活性的机制。在本次综述中，我们讨论了这些调节机制，并展示了如何利用构象变化来设计特定的抑制剂，将蛋白激酶锁定在非活性构象中。此外，我们还强调了最近在监测蛋白激酶中配体诱导的结构变化以及筛选和鉴定稳定酶无活性构象的抑制剂方面的进展。
