效应器
可药性
小分子
蛋白质-蛋白质相互作用
蛋白质组学
计算生物学
DNA微阵列
生物
表观遗传学
血浆蛋白结合
化学
药物发现
蛋白质阵列分析
生物化学
细胞生物学
基因表达
基因
作者
Narkhyun Bae,Monica Viviano,Xuantao Su,Jie Lv,Donghang Cheng,Cari A. Sagum,Sabrina Castellano,Xue Bai,Claire Johnson,Mahmoud Khalil,Jianjun Shen,Kaifu Chen,Haitao Li,Gianluca Sbardella,Mark T. Bedford
标识
DOI:10.1038/nchembio.2377
摘要
The use of protein microarrays containing human methyllysine effector molecules enabled discovery of a potent and selective inhibitor of the interaction of the Tudor-domain-containing protein Spindlin1 with H3K4me3. The discovery of inhibitors of methyl- and acetyl-binding domains has provided evidence for the 'druggability' of epigenetic effector molecules. The small-molecule probe UNC1215 prevents methyl-dependent protein-protein interactions by engaging the aromatic cage of MBT domains and, with lower affinity, Tudor domains. Using a library of tagged UNC1215 analogs, we screened a protein-domain microarray of human methyllysine effector molecules to rapidly detect compounds with new binding profiles with either increased or decreased specificity. Using this approach, we identified a compound (EML405) that acquired a novel interaction with the Tudor-domain-containing protein Spindlin1 (SPIN1). Structural studies facilitated the rational synthesis of SPIN1 inhibitors with increased selectivity (EML631–633), which engage SPIN1 in cells, block its ability to 'read' H3K4me3 marks and inhibit its transcriptional-coactivator activity. Protein microarrays can thus be used as a platform to 'target-hop' and identify small molecules that bind and compete with domain-motif interactions.
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