识别小说增殖蛋白激酶激酶的抑制剂。

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Favata MF, Horiuchi肯塔基州,韩永年EJ, Daulerio AJ, Stradley哒,费用WS, Van Dyk DE,皮特WJ,伯爵RA,霍布斯F,科普兰RA, Magolda RL, Scherle PA, Trzaskos JM

识别小说增殖蛋白激酶激酶的抑制剂。

J生物化学杂志。1998年7月17日,273 (29):18623 - 32。doi: 10.1074 / jbc.273.29.18623。

PubMed ID

9660836 (在PubMed

]

文摘

复合U0126 (1 4-diamino-2 3-dicyano-1 4-bis [2-aminophenylthio]丁二烯)被确认为一种抑制剂的AP-1 transactivation细胞记者分析。U0126也显示出抑制内源性启动子包含AP-1响应元素但并不影响基因缺乏AP-1反应启动子元素。这些影响U0126源于直接抑制增殖作用的蛋白激酶激酶家族成员,MEK-1 MEK-2。抑制是选择性MEK-1和2,U0126显示很少,如果有的话,影响蛋白激酶C的激酶活动,Abl,英国皇家空军,MEKK,兵,物,MKK-3, MKK-4 /克朗,MKK-6, Cdk2,或者到。U0126比较动力学分析和MEK抑制剂PD098059(达德利·d·T。庞,L。德克,美国J。、桥梁、a . J。,Saltiel, a . r . (1995) Proc。国家的。美国私立高中Sci答:92年,7686 - 7689年)表明,U0126和PD098059非竞争性抑制剂对MEK基质,ATP和兵。我们进一步证明这两个化合物结合deltaN3-S218E / S222D MEK相互排斥的方式,表明他们可能共享一个共同的或重叠的结合位点(年代)。 Quantitative evaluation of the steady state kinetics of MEK inhibition by these compounds reveals that U0126 has approximately 100-fold higher affinity for deltaN3-S218E/S222D MEK than does PD098059. We further tested the effects of these compounds on the activity of wild type MEK isolated after activation from stimulated cells. Surprisingly, we observe a significant diminution in affinity of both compounds for wild type MEK as compared with the deltaN3-S218E/S222D mutant enzyme. These results suggest that the affinity of both compounds is mediated by subtle conformational differences between the two activated MEK forms. The MEK affinity of U0126, its selectivity for MEK over other kinases, and its cellular efficacy suggest that this compound will serve as a powerful tool for in vitro and cellular investigations of mitogen-activated protein kinase-mediated signal transduction.

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