Li Ling, Zhang Hailong, Zhang Man, Zhao Mengxi, Feng Lijian, Luo Xiao, Gao Zhenting, Huang Ying, Ardayfio Ophelia, Zhang Ji-Hu, Lin Ying, Fan Hong, Mi Yuan, Li Guobin, Liu Lei, Feng Leying, Luo Fangjun, Teng Lin, Qi Wei, Ottl Johannes, Lingel Andreas, Bussiere Dirksen E, Yu Zhengtian, Atadja Peter, Lu Chris, Li En, Gu Justin, Zhao Kehao
China Novartis Institutes for BioMedical Research, Shanghai, China.
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States of America.
PLoS One. 2017 Jan 10;12(1):e0169855. doi: 10.1371/journal.pone.0169855. eCollection 2017.
Polycomb repressive complex 2 (PRC2), a histone H3 lysine 27 methyltransferase, plays a key role in gene regulation and is a known epigenetics drug target for cancer therapy. The WD40 domain-containing protein EED is the regulatory subunit of PRC2. It binds to the tri-methylated lysine 27 of the histone H3 (H3K27me3), and through which stimulates the activity of PRC2 allosterically. Recently, we disclosed a novel PRC2 inhibitor EED226 which binds to the K27me3-pocket on EED and showed strong antitumor activity in xenograft mice model. Here, we further report the identification and validation of four other EED binders along with EED162, the parental compound of EED226. The crystal structures for all these five compounds in complex with EED revealed a common deep pocket induced by the binding of this diverse set of compounds. This pocket was created after significant conformational rearrangement of the aromatic cage residues (Y365, Y148 and F97) in the H3K27me3 binding pocket of EED, the width of which was delineated by the side chains of these rearranged residues. In addition, all five compounds interact with the Arg367 at the bottom of the pocket. Each compound also displays unique features in its interaction with EED, suggesting the dynamics of the H3K27me3 pocket in accommodating the binding of different compounds. Our results provide structural insights for rational design of novel EED binder for the inhibition of PRC2 complex activity.
多梳抑制复合物2（PRC2）是一种组蛋白H3赖氨酸27甲基转移酶，在基因调控中起关键作用，是一种已知的癌症治疗表观遗传学药物靶点。含WD40结构域的蛋白质EED是PRC2的调节亚基。它与组蛋白H3的三甲基化赖氨酸27（H3K27me3）结合，并通过这种方式变构刺激PRC2的活性。最近，我们公开了一种新型PRC2抑制剂EED226，它与EED上的K27me3口袋结合，并在异种移植小鼠模型中显示出强大的抗肿瘤活性。在这里，我们进一步报告了另外四种EED结合剂以及EED226的母体化合物EED162的鉴定和验证。所有这五种与EED复合的化合物的晶体结构揭示了由这组不同化合物的结合诱导的一个共同的深口袋。这个口袋是在EED的H3K27me3结合口袋中的芳香笼残基（Y365、Y148和F97）发生显著构象重排后形成的，其宽度由这些重排残基的侧链划定。此外，所有五种化合物都与口袋底部的Arg367相互作用。每种化合物在与EED的相互作用中也表现出独特的特征，表明H3K27me3口袋在容纳不同化合物结合时的动态变化。我们的结果为合理设计用于抑制PRC2复合物活性的新型EED结合剂提供了结构见解。
