Genetic selection for dissociative inhibitors of designated protein–protein interactions
Genetic selection for dissociative inhibitors of designated protein–protein interactions
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DOI：
10.1038/78451
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发表时间：
2000-08
影响因子：
46.9
通讯作者：
Sang-Hyun Park;R. Raines
中科院分区：
文献类型：
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作者：
Sang-Hyun Park;R. Raines
许多生物过程依赖于蛋白质-蛋白质相互作用。这些过程包括信号转导、细胞周期调控、基因调控以及病毒组装和复制。此外，许多蛋白质和酶表现出它们作为寡聚体的功能。我们在这里描述了一种有效的手段来筛选大型组合库，并确定分子，阻止靶蛋白在体内的相互作用。这种方法的力量证明了从一个组合库，抑制HIV-1蛋白酶的细胞内二聚化的九个残基肽的鉴定。少于1/10 6的肽这样做。对一种这样的肽的体外生物化学分析表明，它通过将HIV-1蛋白酶解离成单体而起作用，所述单体是无活性的催化剂。通过使肽二聚化进一步增强抑制。这种方法使得能够容易地识别控制细胞过程的新分子。
Many biological processes rely on protein–protein interactions. These processes include signal transduction, cell cycle regulation, gene regulation, and viral assembly and replication. Moreover, many proteins and enzymes manifest their function as oligomers. We describe here an efficient means to sift through large combinatorial libraries and identify molecules that block the interaction of target proteins in vivo. The power of this approach is demonstrated by the identification of nine-residue peptides from a combinatorial library that inhibit the intracellular dimerization of HIV-1 protease. Fewer than 1 in 10 6 peptides do so. In vitro biochemical analyses of one such peptide demonstrate that it acts by dissociating HIV-1 protease into monomers, which are inactive catalysts. Inhibition is enhanced further by dimerizing the peptide. This approach enables the facile identification of new molecules that control cellular processes.