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首页> 外文期刊>Biochemistry >Kinetic mechanism and inhibitor characterization for c-jun-N-terminal kinase 3 alpha 1
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Kinetic mechanism and inhibitor characterization for c-jun-N-terminal kinase 3 alpha 1

机译：c-jun-N-末端激酶3 alpha 1的动力学机理和抑制剂表征

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摘要

c-jun-N-Terminal kinase 3 alpha 1 (JNK3 alpha 1) is a mitogen-activated protein (MAP) kinase family member expressed primarily in the brain that phosphorylates protein transcription factors including c-jun and activating transcription factor 2 (ATF2) upon activation by a variety of stress-based stimuli. In this study, the kinetic mechanism for JNK3 alpha 1 was determined via initial velocity patterns in the presence and absence of both ATP and ATF2 competitive inhibitors. Peptide inhibitors from both ATF2 (peptide 1) and JNK-interacting protein 1 (JIP-1) (peptide 3), derived from the homologous delta-domain JNK docking sequence, inhibited JNK3 alpha 1 activity in a competitive fashion versus ATF2 while being pure noncompetitive toward ATP. In contrast, peptides derived from the phosphoacceptor activation domain on ATF2 (peptides 4 and 5) were recognized neither as substrates nor as inhibitors of JNK3 alpha 1. AMP-PCP and compound 6, a small molecule analinopyrimidine, exhibited pure noncompetitive inhibition versus ATF2 and competitive inhibition versus ATP. Peptide inhibitors based on the delta-domain sites of JIP (3) and ATF2 (1) were not recognized by p38, also of the MAPK family, which may give insight into finding more selective inhibitors for the JNK family of kinases. Collectively these data showed that JNK3 alpha 1 proceeded by a random sequential kinetic mechanism and that the ATP and ATF2 substrate sites were non-interacting. Moreover, these results established the 11-mer JIP peptide (3) as a potent (K-i - 25 +/- 6 nM) competitive inhibitor versus ATF2 in JNK3 alpha 1.
机译：c-jun-N-末端激酶3 alpha 1（JNK3 alpha 1）是一种主要在大脑中表达的促分裂原激活蛋白（MAP）激酶家族成员，可磷酸化包括c-jun和激活转录因子2（ATF2）在内的蛋白质转录因子。在各种基于压力的刺激下被激活。在这项研究中，通过存在和不存在ATP和ATF2竞争性抑制剂的情况下的初始速度模式，确定了JNK3 alpha 1的动力学机制。来自ATF2同源肽域JNK对接序列的ATF2（肽1）和JNK相互作用蛋白1（JIP-1）（肽3）的肽抑制剂与ATF2相比，竞争性地抑制了JNK3 alpha 1的活性，同时它是纯净的对ATP没有竞争力。相反，源自ATF2磷酸受体活化域的肽（肽4和5）既不被识别为JNK3α1的底物也不被抑制剂。AMP-PCP和化合物6（一种小分子Analinopyrimidine）相对于ATF2和ATF2表现出纯的非竞争性抑制作用与ATP竞争性抑制。基于JIP（3）和ATF2（1）δ结构域位点的肽抑制剂未被p38（也属于MAPK家族）识别，这可能有助于发现针对JNK激酶的更多选择性抑制剂。总的来说，这些数据表明JNK3 alpha 1是通过随机顺序动力学机制进行的，并且ATP和ATF2底物位点是不相互作用的。此外，这些结果确定了11-mer JIP肽（3）是JNK3 alpha 1中相对于ATF2的有效（K-1-25 +/- 6 nM）竞争性抑制剂。

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