A versatile synthetic dimerizer for the regulation of protein-protein interactions
A versatile synthetic dimerizer for the regulation of protein-protein interactions
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DOI：
10.1073/pnas.94.20.10618
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发表时间：
1997-09-30
影响因子：
11.1
通讯作者：
Gilman, M
中科院分区：
文献类型：
--
作者：
Amara, JF;Clackson, T;Gilman, M
使用低分子量有机化合物诱导工程蛋白的二聚化或寡聚化在生物研究以及基因和细胞治疗中具有广泛的用途。化学诱导的二聚化可用于激活细胞内信号转导途径或控制二分转录因子的活性。基于天然产物环孢菌素、FK506、雷帕霉素和香豆霉素的二聚化系统已被描述。然而，由于这些化合物的复杂性，通过化学修饰来调整它们的结合或药理学特性是困难的。我们研究了几个由人 FKBP12 配体组成的易于制备、完全合成、细胞可渗透的二聚体家族。这些分子比天然产物二聚体显着降低了复杂性和更大的适应性。我们在此报告了几种新合成化合物在调节工程细胞内两种类型的蛋白质二聚化事件方面的功效——通过工程化 Fas 蛋白二聚化诱导细胞凋亡和通过转录因子融合蛋白二聚化调节转录。特别是一种二聚化剂 AP1510，在所有测试的实验环境中被证明非常有效和通用。
The use of low molecular weight organic compounds to induce dimerization or oligomerization of engineered proteins has wide-ranging utility in biological research as well as in gene and cell therapies, Chemically induced dimerization can be used to activate intracellular signal transduction pathways or to control the activity of a bipartite transcription factor, Dimerizer systems based on the natural products cyclosporin, FK506, rapamycin, and coumermycin have been described. However, owing to the complexity of these compounds, adjusting their binding or pharmacological properties by chemical modification is difficult. We have investigated several families of readily prepared, totally synthetic, cell-permeable dimerizers composed of ligands for human FKBP12. These molecules have significantly reduced complexity and greater adaptability than natural product dimers, We report here the efficacies of several of these new synthetic compounds In regulating two types of protein dimerization events inside engineered cells-induction of apoptosis through dimerization of engineered Fas proteins and regulation of transcription through dimerization of transcription factor fusion proteins, One dimerizer in particular, AP1510, proved to be exceptionally potent and versatile in all experimental contexts tested.