期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 430, 期 10, 页码 1521-1530出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2018.04.001
关键词
crystal structure; DYRK3; PRAS40; harmine; auto-phosphorylation
资金
- National Research Foundation of Korea (NRF) grant - Ministry of Science and ICT [NRF-2016R1A2B2013305, 2016R1A5A1010764, 2017M3A9F6029755]
- Strategic Initiative for Microbiomes in Agriculture and Food - Ministry of Agriculture, Food and Rural Affairs [916006-2]
- National Research Foundation of Korea [2017M3A9F6029755] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Dual-specificity tyrosine-regulated kinases (DYRKs) auto-phosphorylate a critical tyrosine residue in their activation loop and phosphorylate their substrate on serine and threonine residues. The auto-phosphorylation occurs intramolecularly and is a one-off event. DYRK3 is selectively expressed at a high level in hematopoietic cells and attenuates erythroblast development, leading to anemia. In the present study, we determined the crystal structure of the mature form of human DYRK3 in complex with harmine, an ATP competitive inhibitor. The crystal structure revealed a phosphorylation site, residue S350, whose phosphorylation increases the stability of DYRK3 and enhances its kinase activity. In addition, our structural and biochemical assays suggest that the N-terminal auto-phosphorylation accessory domain stabilizes the DYRK3 protein, followed by autophosphorylation of the tyrosine of the activation loop, which is important for kinase activity. Finally, our docking analysis provides information for the design of novel and potent therapeutics to treat anemia. (C) 2018 Elsevier Ltd. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据