5ij7

Structure of Hs/AcPRC2 in complex with a pyridone inhibitorStructure of Hs/AcPRC2 in complex with a pyridone inhibitor

Structural highlights

5ij7 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 2.62Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

SUZ12_HUMAN A chromosomal aberration involving SUZ12 may be a cause of endometrial stromal tumors. Translocation t(7;17)(p15;q21) with JAZF1. The translocation generates the JAZF1-SUZ12 oncogene consisting of the N-terminus part of JAZF1 and the C-terminus part of SUZ12. It is frequently found in all cases of endometrial stromal tumors, except in endometrial stromal sarcomas, where it is rarer.^[1]

Function

SUZ12_HUMAN Polycomb group (PcG) protein. Component 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. 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 and CDKN2A.^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

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^[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Koontz JI, Soreng AL, Nucci M, Kuo FC, Pauwels P, van Den Berghe H, Dal Cin P, Fletcher JA, Sklar J. Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6348-53. PMID:11371647 doi:http://dx.doi.org/10.1073/pnas.101132598
↑ Cao R, Zhang Y. SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Mol Cell. 2004 Jul 2;15(1):57-67. PMID:15225548 doi:10.1016/j.molcel.2004.06.020
↑ Kirmizis A, Bartley SM, Kuzmichev A, Margueron R, Reinberg D, Green R, Farnham PJ. Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27. Genes Dev. 2004 Jul 1;18(13):1592-605. PMID:15231737 doi:10.1101/gad.1200204
↑ Pasini D, Bracken AP, Jensen MR, Lazzerini Denchi E, Helin K. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J. 2004 Oct 13;23(20):4061-71. Epub 2004 Sep 23. PMID:15385962 doi:10.1038/sj.emboj.7600402
↑ Bracken AP, Dietrich N, Pasini D, Hansen KH, Helin K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 2006 May 1;20(9):1123-36. Epub 2006 Apr 17. PMID:16618801 doi:http://dx.doi.org/10.1101/gad.381706
↑ Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, Theilgaard-Monch K, Minucci S, Porse BT, Marine JC, Hansen KH, Helin K. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev. 2007 Mar 1;21(5):525-30. PMID:17344414 doi:http://dx.doi.org/10.1101/gad.415507
↑ Sarma K, Margueron R, Ivanov A, Pirrotta V, Reinberg D. Ezh2 requires PHF1 to efficiently catalyze H3 lysine 27 trimethylation in vivo. Mol Cell Biol. 2008 Apr;28(8):2718-31. doi: 10.1128/MCB.02017-07. Epub 2008 Feb, 19. PMID:18285464 doi:10.1128/MCB.02017-07
↑ 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. Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance. Nat Commun. 2016 Apr 28;7:11384. doi: 10.1038/ncomms11384. PMID:27122193 doi:http://dx.doi.org/10.1038/ncomms11384

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OCA

[1] Koontz JI, Soreng AL, Nucci M, Kuo FC, Pauwels P, van Den Berghe H, Dal Cin P, Fletcher JA, Sklar J. Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6348-53. PMID:11371647 doi:http://dx.doi.org/10.1073/pnas.101132598

[2] Cao R, Zhang Y. SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Mol Cell. 2004 Jul 2;15(1):57-67. PMID:15225548 doi:10.1016/j.molcel.2004.06.020

[3] Kirmizis A, Bartley SM, Kuzmichev A, Margueron R, Reinberg D, Green R, Farnham PJ. Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27. Genes Dev. 2004 Jul 1;18(13):1592-605. PMID:15231737 doi:10.1101/gad.1200204

[4] Pasini D, Bracken AP, Jensen MR, Lazzerini Denchi E, Helin K. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J. 2004 Oct 13;23(20):4061-71. Epub 2004 Sep 23. PMID:15385962 doi:10.1038/sj.emboj.7600402

[5] Bracken AP, Dietrich N, Pasini D, Hansen KH, Helin K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 2006 May 1;20(9):1123-36. Epub 2006 Apr 17. PMID:16618801 doi:http://dx.doi.org/10.1101/gad.381706

[6] Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, Theilgaard-Monch K, Minucci S, Porse BT, Marine JC, Hansen KH, Helin K. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev. 2007 Mar 1;21(5):525-30. PMID:17344414 doi:http://dx.doi.org/10.1101/gad.415507

[7] Sarma K, Margueron R, Ivanov A, Pirrotta V, Reinberg D. Ezh2 requires PHF1 to efficiently catalyze H3 lysine 27 trimethylation in vivo. Mol Cell Biol. 2008 Apr;28(8):2718-31. doi: 10.1128/MCB.02017-07. Epub 2008 Feb, 19. PMID:18285464 doi:10.1128/MCB.02017-07

[8] 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. Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance. Nat Commun. 2016 Apr 28;7:11384. doi: 10.1038/ncomms11384. PMID:27122193 doi:http://dx.doi.org/10.1038/ncomms11384

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