Minimal structural requirements for diglyceride-site directed activators of protein kinase C
Minimal structural requirements for diglyceride-site directed activators of protein kinase C
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DOI：
10.1016/s0040-4020(97)00346-3
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发表时间：
1997-07-21
期刊：
影响因子：
2.1
通讯作者：
Rando, RR
中科院分区：
文献类型：
--
作者：
Marom, M;Parish, CA;Rando, RR
重要的调节酶蛋白激酶C通过（S）-甘油二酯与其调节结构域的相互作用而生理活化。这种相互作用可以通过结构多样的肿瘤促进剂来模拟，所述肿瘤促进剂与甘油二酯沿着共享在边长约为6埃的三角形的顶点处的三个亲水性原子的共同结构特征。本文表明，具有相同的三角形排列但短边的分子也能激活PKC。S-法呢基硫代三唑（FTT）是一种杂环分子，以前显示特异性激活PKC。在本文报道的工作中，FTT系列的结构-活性研究表明，活化需要三个亲水性原子，并且最小活化单元接近于边长为2.4 - 2.7埃的等边三角形。这表明在PKC调节位点存在未预料到的灵活性。基于肿瘤促进剂结构分析的分子间活化模型可以代表PKC活化剂的亲水性原子之间允许的最大距离。(C)1997年爱思唯尔科学有限公司
The important regulatory enzyme protein kinase C is physiologically activated by the interaction of (S)-diglycerides with its regulatory domain. This interaction can he mimicked by the structurally diverse tumor promoters, which share, along with the diglycerides, the common structural feature of three hydrophilic atoms at the vertices of a triangle with sides of approximately 6 Angstrom. It is shown in this article that molecules with the same triangular arrangement of hydrophillic atoms but with shorter sides can also activate PKC. S-Farnesylthiotriazole (FTT) is a heterocyclic molecule previously shown to specifically activate PKC. In the work reported here, structure-activity studies in the FTT series reveal that three hydrophilic atoms are required for activation, and that the minimal activation unit is close to an equilateral triangle with sides of between 2.4 - 2.7 Angstrom. This demonstrates that there is an unanticipated flexibility at the PKC regulatory site. The intermolecular activation model based on structural analysis of the tumor promoters may represent the maximum distances allowed between the hydrophilic atoms of a PKC activator. (C) 1997 Elsevier Science Ltd.