Crystal structure of human mono-phosphorylated ERK1 at Tyr204
Crystal structure of human mono-phosphorylated ERK1 at Tyr204
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DOI：
10.1016/j.bbrc.2008.10.127
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发表时间：
2008-12-26
影响因子：
3.1
通讯作者：
Tada, Toshiji
中科院分区：
文献类型：
--
作者：
Kinoshita, Takayoshi;Yoshida, Ikuyo;Tada, Toshiji
细胞外信号调节激酶（ERK）是MAP激酶家族的一员，可以调节多种细胞反应。ERK1和ERK2具有明显相似的氨基酸序列，但表现出不同的生理功能。与ERK2一样，ERK1在大肠杆菌生产过程中在激活环中的Tyr204位点被自动和单磷酸化，导致其基础水平的活性，与在Thr202和Tyr204位点双磷酸化的全活性ERK1相比，其活性约低500倍。晶体结构表明，单磷酸化ERK1激酶具有不同于非磷酸化（无活性）和双磷酸化（全活性）形式的新构象。c -螺旋和激活环的特征结构特征可能有助于单磷酸化ERK1的基础活性。与ERK2相比，ERK1的结构解剖表明，D-motif结合位点和背面结合位点的结构差异可能是开发选择性ERK1/ERK2抑制剂的目标。(C) 2008爱思唯尔公司版权所有。
Extracellular signal-regulated kinase (ERK) is a member of the MAP kinase family, and can regulate several cellular responses. The isoforms ERK1 and ERK2 have markedly similar amino acid sequences, but exhibit distinctive physiological functions. As well as ERK2, ERK1 was auto- and mono-phosphorylated at Tyr204 in the activation loop during Escherichia coli production, resulting in basal level activity, approximately 500-fold less compared with fully-active ERK1 dual-phosphorylated at Thr202 and Tyr204. Crystal structure demonstrated that the mono-phosphorylated ERK1 kinase possessed a novel conformation distinguishable from the un-phosphorylated (inactive) and the dual-phosphorylated (full-active) forms. The characteristic Structural features in both the C-helix and the activation loop likely contribute to the basal activity of the mono-phosphorylated ERK1. The Structural dissection of ERK1 compared to ERK2 Suggests that the Structural differences in the D-motif binding site and in the backside binding site are putative targets for development of selective ERK1/ERK2 inhibitors. (C) 2008 Elsevier Inc. All rights reserved.