5IJ7

Structure of Hs/AcPRC2 in complex with a pyridone inhibitor

5IJ7 の概要

• エントリーDOI: 10.2210/pdb5ij7/pdb
• 関連するPDBエントリー: 5IJ8
• 分子名称: Enhancer of Zeste Homolog 2 (EZH2),Histone-lysine N-methyltransferase EZH2, Polycomb protein EED, Polycomb protein SUZ12, ... (6 entities in total)
• 機能のキーワード: lysine methyltransferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Anolis carolinensis (Green anole); 詳細
• 細胞内の位置: Nucleus : Q15910 O75530 Q15022
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 275962.15

構造登録者

Gajiwala, K.S.,Brooun, A.,Deng, Y.-L.,Liu, W. (登録日: 2016-03-01, 公開日: 2016-05-04, 最終更新日: 2024-10-30)

主引用文献

Brooun, A.,Gajiwala, K.S.,Deng, Y.L.,Liu, W.,Bolanos, B.,Bingham, P.,He, Y.A.,Diehl, W.,Grable, N.,Kung, P.P.,Sutton, S.,Maegley, K.A.,Yu, X.,Stewart, A.E.
Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance.
Nat Commun, 7:11384-11384, 2016

PubMed Abstract: Polycomb repressive complex 2 (PRC2) mediates gene silencing through chromatin reorganization by methylation of histone H3 lysine 27 (H3K27). Overexpression of the complex and point mutations in the individual subunits of PRC2 have been shown to contribute to tumorigenesis. Several inhibitors of the PRC2 activity have shown efficacy in EZH2-mutated lymphomas and are currently in clinical development, although the molecular basis of inhibitor recognition remains unknown. Here we report the crystal structures of the inhibitor-bound wild-type and Y641N PRC2. The structures illuminate an important role played by a stretch of 17 residues in the N-terminal region of EZH2, we call the activation loop, in the stimulation of the enzyme activity, inhibitor recognition and the potential development of the mutation-mediated drug resistance. The work presented here provides new avenues for the design and development of next-generation PRC2 inhibitors through establishment of a structure-based drug design platform.

PubMed: 27122193
DOI: 10.1038/ncomms11384

実験手法

X-RAY DIFFRACTION (2.62 Å)