Targeting GSK3 from Ustilago maydis: Type-II Kinase Inhibitors as Potential Antifungals
Targeting GSK3 from Ustilago maydis: Type-II Kinase Inhibitors as Potential Antifungals
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DOI：
10.1021/cb300128b
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发表时间：
2012-07-01
影响因子：
4
通讯作者：
Rauh, Daniel
中科院分区：
文献类型：
--
作者：
Gruetter, Christian;Simard, Jeffrey R.;Rauh, Daniel
蛋白激酶是几乎所有生物体中细胞过程复杂调节的关键酶。由于这个原因，蛋白激酶代表有吸引力的目标，以停止真核病原体，如原生动物和真菌的生长。然而，使用激酶抑制剂来对抗这些生物体面临着一些挑战，因为它们中的大多数是非选择性的，并且也会影响关键的宿主激酶。在这里，我们提出的X-射线结构的糖原合成酶激酶3从真菌植物病原体玉米黑粉菌（UmGSK 3）和它的抑制II型激酶抑制剂。尽管人类和真菌之间的这种重要的激酶的变体的序列同源性很高，我们发现其活性位点的构象可塑性有很大的差异。诱导这种构象变化的化合物可用于选择性抑制真菌激酶。这项研究是如何通过识别和解决蛋白激酶的失活状态来实现抑制剂的物种特异性选择性的一个例子。除此之外，我们的研究通过揭示这个重要激酶家族的一种以前未知的非活性构象，对UmGSK 3的分子可塑性提供了有趣的见解。
Protein kinases are key enzymes in the complex regulation of cellular processes in almost all living organisms. For this reason, protein kinases represent attractive targets to stop the growth of eukaryotic pathogens such as protozoa and fungi. However, using kinase inhibitors to fight against these organisms bears several challenges since most of them are unselective and will also affect crucial host kinases. Here we present the X-ray structure of glycogen synthase kinase 3 from the fungal plant pathogen Ustilago maydis (UmGSK3) and its inhibition by type-II kinase inhibitors. Despite the high sequence homology between the human and the fungal variant of this vital kinase, we found substantial differences in the conformational plasticity of their active sites. Compounds that induced such conformational changes could be used to selectively inhibit the fungal kinase. This study serves as an example of how species-specific selectivity of inhibitors can be achieved by identifying and addressing the inactive state of a protein kinase. In addition to this, our study gives interesting insights into the molecular plasticity of UmGSK3 by revealing a previously unknown inactive conformation of this important kinase family.