5K0M

Targeting the PRC2 complex through a novel protein-protein interaction inhibitor of EED

Summary for 5K0M

• Entry DOI: 10.2210/pdb5k0m/pdb
• Descriptor: Polycomb protein EED, (3R,4S)-1-[(1S)-7-fluoro-2,3-dihydro-1H-inden-1-yl]-N,N-dimethyl-4-{4-[4-(methylsulfonyl)piperazin-1-yl]phenyl}pyrrolidin-3-amine (3 entities in total)
• Functional Keywords: wd40 prc2, protein binding
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O75530
• Total number of polymer chains: 1
• Total formula weight: 43423.57

Authors

Jakob, C.G.,Bigelow, L.J.,Zhu, H.,Sun, C. (deposition date: 2016-05-17, release date: 2017-01-25, Last modification date: 2023-09-27)

Primary citation

He, Y.,Selvaraju, S.,Curtin, M.L.,Jakob, C.G.,Zhu, H.,Comess, K.M.,Shaw, B.,The, J.,Lima-Fernandes, E.,Szewczyk, M.M.,Cheng, D.,Klinge, K.L.,Li, H.Q.,Pliushchev, M.,Algire, M.A.,Maag, D.,Guo, J.,Dietrich, J.,Panchal, S.C.,Petros, A.M.,Sweis, R.F.,Torrent, M.,Bigelow, L.J.,Senisterra, G.,Li, F.,Kennedy, S.,Wu, Q.,Osterling, D.J.,Lindley, D.J.,Gao, W.,Galasinski, S.,Barsyte-Lovejoy, D.,Vedadi, M.,Buchanan, F.G.,Arrowsmith, C.H.,Chiang, G.G.,Sun, C.,Pappano, W.N.
The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex.
Nat. Chem. Biol., 13:389-395, 2017

PubMed Abstract: Polycomb repressive complex 2 (PRC2) is a regulator of epigenetic states required for development and homeostasis. PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), which leads to gene silencing, and is dysregulated in many cancers. The embryonic ectoderm development (EED) protein is an essential subunit of PRC2 that has both a scaffolding function and an H3K27me3-binding function. Here we report the identification of A-395, a potent antagonist of the H3K27me3 binding functions of EED. Structural studies demonstrate that A-395 binds to EED in the H3K27me3-binding pocket, thereby preventing allosteric activation of the catalytic activity of PRC2. Phenotypic effects observed in vitro and in vivo are similar to those of known PRC2 enzymatic inhibitors; however, A-395 retains potent activity against cell lines resistant to the catalytic inhibitors. A-395 represents a first-in-class antagonist of PRC2 protein-protein interactions (PPI) for use as a chemical probe to investigate the roles of EED-containing protein complexes.

PubMed: 28135237
DOI: 10.1038/nchembio.2306

Experimental method

X-RAY DIFFRACTION (1.83 Å)