5ij8

Structure of the primary oncogenic mutant Y641N Hs/AcPRC2 in complex with a pyridone inhibitor

spinqualitylabelsall models 5ij8, resolution 2.99Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5ij8 is a 6 chain structure with sequence from Anolis carolinensis and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.99Å Ligands: 6BN, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease EZH2_HUMAN Weaver syndrome. The disease is caused by mutations affecting the gene represented in this entry. Function EZH2_HUMAN Polycomb group (PcG) protein. Catalytic subunit of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' (H3K9me) and 'Lys-27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene. Able to mono-, di- and trimethylate 'Lys-27' of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively. Compared to EZH2-containing complexes, it is more abundant in embryonic stem cells and plays a major role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation. The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems. Genes repressed by the PRC2/EED-EZH2 complex include HOXC8, HOXA9, MYT1, CDKN2A and retinoic acid target genes. EZH2 can also methylate non-histone proteins such as the transcription factor GATA4 and the nuclear receptor RORA. G1KPH4_ANOCA Publication Abstract from PubMed 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. Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance.,Brooun A, Gajiwala KS, Deng YL, Liu W, Bolanos B, Bingham P, He YA, Diehl W, Grable N, Kung PP, Sutton S, Maegley KA, Yu X, Stewart AE Nat Commun. 2016 Apr 28;7:11384. doi: 10.1038/ncomms11384. PMID:27122193 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Polycomb complex proteins 3D structures

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