4MI0

Human Enhancer of Zeste (Drosophila) Homolog 2(EZH2)

4MI0 の概要

• エントリーDOI: 10.2210/pdb4mi0/pdb
• 分子名称: Histone-lysine N-methyltransferase EZH2, ZINC ION, UNKNOWN ATOM OR ION, ... (4 entities in total)
• 機能のキーワード: ezh2, gene regulation, chromatin modification, histone methyltransferase, transcription, gene silencing, polycomb repressive complex 2, structural genomics, structural genomics consortium, sgc, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus : Q15910
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 27098.87

構造登録者

Dong, A.,Zeng, H.,He, H.,Wernimont, A.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,Brown, P.J.,Wu, H.,Structural Genomics Consortium (SGC) (登録日: 2013-08-30, 公開日: 2013-09-25, 最終更新日: 2024-02-28)

主引用文献

Wu, H.,Zeng, H.,Dong, A.,Li, F.,He, H.,Senisterra, G.,Seitova, A.,Duan, S.,Brown, P.J.,Vedadi, M.,Arrowsmith, C.H.,Schapira, M.
Structure of the catalytic domain of EZH2 reveals conformational plasticity in cofactor and substrate binding sites and explains oncogenic mutations.
Plos One, 8:e83737-e83737, 2013

PubMed Abstract: Polycomb repressive complex 2 (PRC2) is an important regulator of cellular differentiation and cell type identity. Overexpression or activating mutations of EZH2, the catalytic component of the PRC2 complex, are linked to hyper-trimethylation of lysine 27 of histone H3 (H3K27me3) in many cancers. Potent EZH2 inhibitors that reduce levels of H3K27me3 kill mutant lymphoma cells and are efficacious in a mouse xenograft model of malignant rhabdoid tumors. Unlike most SET domain methyltransferases, EZH2 requires PRC2 components, SUZ12 and EED, for activity, but the mechanism by which catalysis is promoted in the PRC2 complex is unknown. We solved the 2.0 Å crystal structure of the EZH2 methyltransferase domain revealing that most of the canonical structural features of SET domain methyltransferase structures are conserved. The site of methyl transfer is in a catalytically competent state, and the structure clarifies the structural mechanism underlying oncogenic hyper-trimethylation of H3K27 in tumors harboring mutations at Y641 or A677. On the other hand, the I-SET and post-SET domains occupy atypical positions relative to the core SET domain resulting in incomplete formation of the cofactor binding site and occlusion of the substrate binding groove. A novel CXC domain N-terminal to the SET domain may contribute to the apparent inactive conformation. We propose that protein interactions within the PRC2 complex modulate the trajectory of the post-SET and I-SET domains of EZH2 in favor of a catalytically competent conformation.

PubMed: 24367611
DOI: 10.1371/journal.pone.0083737

実験手法

X-RAY DIFFRACTION (2 Å)