Structural insights into trypanosomatid Mnk kinase orthologues (kMnks) suggest altered mechanism in the kinase domain.

IF 7.7 1区 化学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Shilpa Sharma, Mrityunjay Singh, Adarsh Kumar Chiranjivi, Anica Dadwal, Shubbir Ahmed, Shailendra Asthana, Supratik Das
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引用次数: 0

Abstract

Mitogen-activated protein kinase (MAPK) interacting protein kinases (Mnk1 and Mnk2) mediated phosphorylation of the eukaryotic initiation factor eIF4E is an important translation initiation control, in Mnk-mediated oncogenic activity and other disease conditions. Thus, Mnk kinases are an important target for therapy. Trypanosomatids are a class of kinetoplastids, some of which are protozoan parasites and cause diseases in humans. While protein translation initiation is well understood in eukaryotes and prokaryotes, there is a lack of sufficient structural information of this process in trypanosomatids. Here, we report that trypanosomatids have one orthologue of Mnk kinase with low overall sequence homology but high homology in the kinase domain and an additional C-terminal domain containing putative calmodulin binding site(s). We show that while many of the domains and motifs are conserved, homology modeling/structure prediction, docking analysis and molecular dynamics simulation studies suggest that trypanosomatid kMnk kinases, kinase domains are present in DFG-in conformation as opposed to the auto-inhibited DFD-out conformation of un-phosphorylated human Mnk1. Furthermore, we observed that several regulatory features are different in trypanosomatid kMnk kinases. Our study indicates that mechanism and regulation in the kinase domain of trypanosomatid kMnks are likely to be altered, and that they can be important drug targets.

对锥虫 Mnk 激酶同源物(kMnks)的结构研究表明,激酶结构域的机制发生了改变。
丝裂原活化蛋白激酶(MAPK)相互作用蛋白激酶(Mnk1 和 Mnk2)介导的真核生物起始因子 eIF4E 磷酸化是一种重要的翻译起始控制,在 Mnk 介导的致癌活动和其他疾病中起着重要作用。因此,Mnk 激酶是一个重要的治疗靶点。锥虫是一类动粒体,其中一些是原生动物寄生虫,可导致人类疾病。虽然人们对真核生物和原核生物的蛋白质翻译起始过程非常了解,但对锥虫的这一过程却缺乏足够的结构信息。在这里,我们报告了锥虫有一个 Mnkk 激酶的直向同源物,其整体序列同源性较低,但激酶结构域的同源性较高,另外一个 C 端结构域含有假定的钙调素结合位点。我们的研究表明,虽然许多结构域和基序是保守的,但同源建模/结构预测、对接分析和分子动力学模拟研究表明,锥虫 kMnk 激酶的激酶结构域是以 DFG-in 构象存在的,而不是未磷酸化的人类 Mnk1 的自动抑制 DFD-out 构象。此外,我们还观察到锥虫 kMnk 激酶的几个调控特征有所不同。我们的研究表明,锥虫kMnk激酶结构域的机制和调控可能发生了改变,它们可能成为重要的药物靶标。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
International Journal of Biological Macromolecules
International Journal of Biological Macromolecules 生物-生化与分子生物学
CiteScore
13.70
自引率
9.80%
发文量
2728
审稿时长
64 days
期刊介绍: The International Journal of Biological Macromolecules is a well-established international journal dedicated to research on the chemical and biological aspects of natural macromolecules. Focusing on proteins, macromolecular carbohydrates, glycoproteins, proteoglycans, lignins, biological poly-acids, and nucleic acids, the journal presents the latest findings in molecular structure, properties, biological activities, interactions, modifications, and functional properties. Papers must offer new and novel insights, encompassing related model systems, structural conformational studies, theoretical developments, and analytical techniques. Each paper is required to primarily focus on at least one named biological macromolecule, reflected in the title, abstract, and text.
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