5H14

EED in complex with an allosteric PRC2 inhibitor EED666

Summary for 5H14

• Entry DOI: 10.2210/pdb5h14/pdb
• Related: 5H13 5H15 5H17 5H19 5H24 5H25
• Descriptor: Polycomb protein EED, Histone-lysine N-methyltransferase EZH2, GLYCEROL, ... (5 entities in total)
• Functional Keywords: eed, prc2, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus: O75530 Q15910
• Total number of polymer chains: 4
• Total formula weight: 92837.80

Authors

Zhao, K.,Zhao, M.,Luo, X.,Zhang, H. (deposition date: 2016-10-08, release date: 2017-01-25, Last modification date: 2024-10-23)

Primary citation

Li, L.,Zhang, H.,Zhang, M.,Zhao, M.,Feng, L.,Luo, X.,Gao, Z.,Huang, Y.,Ardayfio, O.,Zhang, J.H.,Lin, Y.,Fan, H.,Mi, Y.,Li, G.,Liu, L.,Feng, L.,Luo, F.,Teng, L.,Qi, W.,Ottl, J.,Lingel, A.,Bussiere, D.E.,Yu, Z.,Atadja, P.,Lu, C.,Li, E.,Gu, J.,Zhao, K.
Discovery and Molecular Basis of a Diverse Set of Polycomb Repressive Complex 2 Inhibitors Recognition by EED
PLoS ONE, 12:e0169855-e0169855, 2017

PubMed Abstract: 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.

PubMed: 28072869
DOI: 10.1371/journal.pone.0169855

Experimental method

X-RAY DIFFRACTION (1.9 Å)