Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.
Department of Pharmacology and Toxicology, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
J Proteome Res. 2017 Oct 6;16(10):3766-3773. doi: 10.1021/acs.jproteome.7b00451. Epub 2017 Sep 28.
WD40 repeat (WDR) domains are protein interaction scaffolds that represent one of the largest protein families in human, and a first WDR inhibitor-an allosteric antagonist of polycomb repressive complex 2-just entered the clinic. A systematic analysis of the CORUM database of protein complexes shows that WDR is the most represented domain in transcriptional regulation and one of the most prevalent in the ubiquitin proteasome system, two pathways of high relevance to drug discovery. Parsing the literature and the vulnerability of cancer cell lines to CRISPR knockout indicates that WDR proteins are targets of interest in oncology and other disease areas. A quantitative analysis of WDR structures reveals that druggable binding pockets can be found on multiple surfaces of these multifaceted protein interaction platforms. These data support the development of chemical probes to further interrogate WDR proteins as an emerging therapeutic target class.
WD40 重复（WDR）结构域是蛋白质相互作用的支架，是人类最大的蛋白质家族之一，首个 WDR 抑制剂——多梳抑制复合物 2 的别构拮抗剂刚刚进入临床。对蛋白质复合物 CORUM 数据库的系统分析表明，WDR 是转录调控中最具代表性的结构域之一，也是泛素蛋白酶体系统中最常见的结构域之一，这两个途径与药物发现密切相关。对文献的解析以及癌细胞系对 CRISPR 敲除的敏感性表明，WDR 蛋白是肿瘤学和其他疾病领域的关注靶点。对 WDR 结构的定量分析表明，在这些多面的蛋白质相互作用平台的多个表面上可以找到可成药的结合口袋。这些数据支持开发化学探针，以进一步研究 WDR 蛋白作为一个新兴的治疗靶点。
