5U62

Crystal structure of EED in complex with H3K27Me3 peptide and 6-(benzo[d][1,3]dioxol-4-ylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-3-amine

5U62 の概要

• エントリーDOI: 10.2210/pdb5u62/pdb
• 関連するPDBエントリー: 5U5H 5U5K 5U5T
• 分子名称: Polycomb protein EED, Histone-lysine N-methyltransferase EZH2, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: eed, fragment-based generation, oncology, transcription-transferase complex, transcription/transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Nucleus: O75530 Q15910
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 93027.71

構造登録者

Bussiere, D.,Shu, W. (登録日: 2016-12-07, 公開日: 2017-01-11, 最終更新日: 2024-03-06)

主引用文献

Lingel, A.,Sendzik, M.,Huang, Y.,Shultz, M.D.,Cantwell, J.,Dillon, M.P.,Fu, X.,Fuller, J.,Gabriel, T.,Gu, J.,Jiang, X.,Li, L.,Liang, F.,McKenna, M.,Qi, W.,Rao, W.,Sheng, X.,Shu, W.,Sutton, J.,Taft, B.,Wang, L.,Zeng, J.,Zhang, H.,Zhang, M.,Zhao, K.,Lindvall, M.,Bussiere, D.E.
Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase.
J. Med. Chem., 60:415-427, 2017

PubMed Abstract: PRC2 is a multisubunit methyltransferase involved in epigenetic regulation of early embryonic development and cell growth. The catalytic subunit EZH2 methylates primarily lysine 27 of histone H3, leading to chromatin compaction and repression of tumor suppressor genes. Inhibiting this activity by small molecules targeting EZH2 was shown to result in antitumor efficacy. Here, we describe the optimization of a chemical series representing a new class of PRC2 inhibitors which acts allosterically via the trimethyllysine pocket of the noncatalytic EED subunit. Deconstruction of a larger and complex screening hit to a simple fragment-sized molecule followed by structure-guided regrowth and careful property modulation were employed to yield compounds which achieve submicromolar inhibition in functional assays and cellular activity. The resulting molecules can serve as a simplified entry point for lead optimization and can be utilized to study this new mechanism of PRC2 inhibition and the associated biology in detail.

PubMed: 27992714
DOI: 10.1021/acs.jmedchem.6b01473

実験手法

X-RAY DIFFRACTION (1.9 Å)