7KXT

Crystal structure of human EED

Summary for 7KXT

• Entry DOI: 10.2210/pdb7kxt/pdb
• Descriptor: Polycomb protein EED, 1-[(4-fluorophenyl)methyl]-N-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-1H-benzimidazol-2-amine, UNKNOWN ATOM OR ION, ... (4 entities in total)
• Functional Keywords: eed, wd40, structural genomics, structural genomics consortium, sgc, gene regulation
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 93233.84

Authors

Zhu, L.,Dong, A.,Du, D.,Liu, Y.,Luo, C.,Arrowsmith, C.H.,Edwards, A.M.,Min, J.,Structural Genomics Consortium (SGC) (deposition date: 2020-12-04, release date: 2021-02-24, Last modification date: 2023-10-18)

Primary citation

Du, D.,Xu, D.,Zhu, L.,Stazi, G.,Zwergel, C.,Liu, Y.,Luo, Z.,Li, Y.,Zhang, Y.,Zhu, K.,Ding, Y.,Liu, J.,Fan, S.,Zhao, K.,Zhang, N.,Kong, X.,Jiang, H.,Chen, K.,Zhao, K.,Valente, S.,Min, J.,Duan, W.,Luo, C.
Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2-EED Interaction.
J.Med.Chem., 64:8194-8207, 2021

PubMed Abstract: Disruption of EZH2-embryonic ectoderm development (EED) protein-protein interaction (PPI) is a new promising cancer therapeutic strategy. We have previously reported the discovery of astemizole, a small-molecule inhibitor targeting the EZH2-EED PPI. Herein, we report the cocrystal structure of EED in complex with astemizole at 2.15 Å. The structure elucidates the detailed binding mode of astemizole to EED and provides a structure-guided design for the discovery of a novel EZH2-EED interaction inhibitor, DC-PRC2in-01, with an affinity of 4.56 μM. DC-PRC2in-01 destabilizes the PRC2 complex, thereby leading to the degradation of PRC2 core proteins and the decrease of global H3K27me3 levels in cancer cells. The proliferation of PRC2-driven lymphomas cells is effectively inhibited, and the cell cycle is arrested in the G0/G1 phase. Together, these data demonstrate that DC-PRC2in-01 could be an effective chemical probe for investigating the PRC2-related physiology and pathology and providing a promising chemical scaffold for further development.

PubMed: 34077206
DOI: 10.1021/acs.jmedchem.0c02261

Experimental method

X-RAY DIFFRACTION (2.15 Å)