5U5T
Crystal structure of EED in complex with H3K27Me3 peptide and 3-(benzo[d][1,3]dioxol-4-ylmethyl)piperidine-1-carboximidamide
Summary for 5U5T
| Entry DOI | 10.2210/pdb5u5t/pdb |
| Related | 5U5H 5U5K 5U62 |
| Descriptor | Polycomb protein EED, Histone-lysine N-methyltransferase EZH2, (3R)-3-[(2H-1,3-benzodioxol-4-yl)methyl]piperidine-1-carboximidamide, ... (5 entities in total) |
| Functional Keywords | eed, fragment-based generation, oncology, transcription-transferase complex, transcription/transferase |
| Biological source | Homo sapiens (Human) More |
| Cellular location | Nucleus: O75530 Q15910 |
| Total number of polymer chains | 4 |
| Total formula weight | 92915.63 |
| Authors | Bussiere, D.,Shu, W. (deposition date: 2016-12-07, release date: 2017-01-11, Last modification date: 2024-03-06) |
| Primary citation | Lingel, A.,Sendzik, M.,Huang, Y.,Shultz, M.D.,Cantwell, J.,Dillon, M.P.,Fu, X.,Fuller, J.,Gabriel, T.,Gu, J.,Jiang, X.,Li, L.,Liang, F.,McKenna, M.,Qi, W.,Rao, W.,Sheng, X.,Shu, W.,Sutton, J.,Taft, B.,Wang, L.,Zeng, J.,Zhang, H.,Zhang, M.,Zhao, K.,Lindvall, M.,Bussiere, D.E. Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase. J. Med. Chem., 60:415-427, 2017 Cited by PubMed Abstract: PRC2 is a multisubunit methyltransferase involved in epigenetic regulation of early embryonic development and cell growth. The catalytic subunit EZH2 methylates primarily lysine 27 of histone H3, leading to chromatin compaction and repression of tumor suppressor genes. Inhibiting this activity by small molecules targeting EZH2 was shown to result in antitumor efficacy. Here, we describe the optimization of a chemical series representing a new class of PRC2 inhibitors which acts allosterically via the trimethyllysine pocket of the noncatalytic EED subunit. Deconstruction of a larger and complex screening hit to a simple fragment-sized molecule followed by structure-guided regrowth and careful property modulation were employed to yield compounds which achieve submicromolar inhibition in functional assays and cellular activity. The resulting molecules can serve as a simplified entry point for lead optimization and can be utilized to study this new mechanism of PRC2 inhibition and the associated biology in detail. PubMed: 27992714DOI: 10.1021/acs.jmedchem.6b01473 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.6 Å) |
Structure validation
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