5IJ8
Structure of the primary oncogenic mutant Y641N Hs/AcPRC2 in complex with a pyridone inhibitor
Summary for 5IJ8
| Entry DOI | 10.2210/pdb5ij8/pdb |
| Related | 5IJ7 |
| Descriptor | Enhancer of Zeste Homolog 2 (EZH2),Histone-lysine N-methyltransferase EZH2, Polycomb protein EED, Polycomb protein SUZ12, ... (5 entities in total) |
| Functional Keywords | lysine methyltransferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Anolis carolinensis (Green anole) More |
| Cellular location | Nucleus : Q15910 O75530 Q15022 |
| Total number of polymer chains | 6 |
| Total formula weight | 275864.01 |
| Authors | Gajiwala, K.S.,Brooun, A.,Deng, Y.-L.,Liu, W. (deposition date: 2016-03-01, release date: 2016-05-04, Last modification date: 2024-11-06) |
| Primary citation | Brooun, A.,Gajiwala, K.S.,Deng, Y.L.,Liu, W.,Bolanos, B.,Bingham, P.,He, Y.A.,Diehl, W.,Grable, N.,Kung, P.P.,Sutton, S.,Maegley, K.A.,Yu, X.,Stewart, A.E. Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance. Nat Commun, 7:11384-11384, 2016 Cited by PubMed Abstract: Polycomb repressive complex 2 (PRC2) mediates gene silencing through chromatin reorganization by methylation of histone H3 lysine 27 (H3K27). Overexpression of the complex and point mutations in the individual subunits of PRC2 have been shown to contribute to tumorigenesis. Several inhibitors of the PRC2 activity have shown efficacy in EZH2-mutated lymphomas and are currently in clinical development, although the molecular basis of inhibitor recognition remains unknown. Here we report the crystal structures of the inhibitor-bound wild-type and Y641N PRC2. The structures illuminate an important role played by a stretch of 17 residues in the N-terminal region of EZH2, we call the activation loop, in the stimulation of the enzyme activity, inhibitor recognition and the potential development of the mutation-mediated drug resistance. The work presented here provides new avenues for the design and development of next-generation PRC2 inhibitors through establishment of a structure-based drug design platform. PubMed: 27122193DOI: 10.1038/ncomms11384 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.99 Å) |
Structure validation
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