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首页> 外文期刊>Chemistry & biology >A genome-wide overexpression screen in yeast for small-molecule target identification
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A genome-wide overexpression screen in yeast for small-molecule target identification

机译：酵母中的全基因组过表达筛选，用于小分子靶标鉴定

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摘要

We describe a multicopy gene suppression screen of drug sensitivity in Saccharomyces cerevisiae that facilitates the identification of cellular targets of small molecules. An array of yeast transformants harboring a multicopy yeast genomic library was screened for resistance to growth inhibitors. Comparison of array growth patterns for several such inhibitors allowed the differentiation of general and molecule-specific genetic suppressors. Specific resistance to phenyl-aminopyrimidine (1), an inhibitor identified from a kinase-directed library, was associated with the over-expression of Pkc1 and a subset of downstream kinases. Components of two other pathways (pheromone response/filamentous growth and Pho85 kinase) that genetically interact with the PKC1 MAPK signaling cascade were also identified. Consistent with the suppression screen, inhibitor 1 bound to Pkc1 in yeast cell lysate and inhibited its activity in vitro. These results demonstrate the utility of this approach for the rapid deconvolution of small-molecule targets.
机译：我们描述了酿酒酵母中的药物敏感性的多拷贝基因抑制筛选，它有助于识别小分子的细胞靶标。筛选具有多拷贝酵母基因组文库的一系列酵母转化体对生长抑制剂的抗性。比较几种这样的抑制剂的阵列生长模式可以区分一般的和分子特异性的基因抑制剂。从激酶导向的文库中鉴定出的一种抑制剂，对苯基氨基嘧啶（1）的特异性抗性与Pkc1和下游激酶子集的过表达有关。还确定了与PKC1 MAPK信号级联反应发生遗传相互作用的其他两个途径的组成部分（信息素应答/丝状生长和Pho85激酶）。与抑制筛选一致，抑制剂1与酵母细胞裂解物中的Pkc1结合并在体外抑制了其活性。这些结果证明了该方法可用于小分子靶的快速去卷积。

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