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5wp3

From Proteopedia

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Current revision

Crystal Structure of EED in complex with EB22

Structural highlights

5wp3 is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.55Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

EED_HUMAN Polycomb group (PcG) protein. Component of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' and 'Lys-27' of histone H3, leading to transcriptional repression of the affected target gene. Also recognizes 'Lys-26' trimethylated histone H1 with the effect of inhibiting PRC2 complex methyltransferase activity on nucleosomal histone H3 'Lys-27', whereas H3 'Lys-27' recognition has the opposite effect, enabling the propagation of this repressive mark. 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.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9]

Publication Abstract from PubMed

The polycomb repressive complex 2 (PRC2) histone methyltransferase plays a central role in epigenetic regulation in development and in cancer, and hence to interrogate its role in a specific developmental transition, methods are needed for disrupting function of the complex with high temporal and spatial precision. The catalytic and substrate recognition functions of PRC2 are coupled by binding of the N-terminal helix of the Ezh2 methylase to an extended groove on the EED trimethyl lysine binding subunit. Disrupting PRC2 function can in principle be achieved by blocking this single interaction, but there are few approaches for blocking specific protein-protein interactions in living cells and organisms. Here, we describe the computational design of proteins that bind to the EZH2 interaction site on EED with subnanomolar affinity in vitro and form tight and specific complexes with EED in living cells. Induction of the EED binding proteins abolishes H3K27 methylation in human embryonic stem cells (hESCs) and at all but the earliest stage blocks self-renewal, pinpointing the first critical repressive H3K27me3 marks in development.

First critical repressive H3K27me3 marks in embryonic stem cells identified using designed protein inhibitor.,Moody JD, Levy S, Mathieu J, Xing Y, Kim W, Dong C, Tempel W, Robitaille AM, Dang LT, Ferreccio A, Detraux D, Sidhu S, Zhu L, Carter L, Xu C, Valensisi C, Wang Y, Hawkins RD, Min J, Moon RT, Orkin SH, Baker D, Ruohola-Baker H Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):10125-10130. doi:, 10.1073/pnas.1706907114. Epub 2017 Sep 1. PMID:28864533^[10]

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

References

↑ Sewalt RG, van der Vlag J, Gunster MJ, Hamer KM, den Blaauwen JL, Satijn DP, Hendrix T, van Driel R, Otte AP. Characterization of interactions between the mammalian polycomb-group proteins Enx1/EZH2 and EED suggests the existence of different mammalian polycomb-group protein complexes. Mol Cell Biol. 1998 Jun;18(6):3586-95. PMID:9584199
↑ van der Vlag J, Otte AP. Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation. Nat Genet. 1999 Dec;23(4):474-8. PMID:10581039 doi:10.1038/70602
↑ Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 2003 Oct 15;22(20):5323-35. PMID:14532106 doi:10.1093/emboj/cdg542
↑ 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
↑ 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
↑ 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
↑ Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, de Launoit Y, Fuks F. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006 Feb 16;439(7078):871-4. Epub 2005 Dec 14. PMID:16357870 doi:10.1038/nature04431
↑ 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
↑ Xu C, Bian C, Yang W, Galka M, Ouyang H, Chen C, Qiu W, Liu H, Jones AE, Mackenzie F, Pan P, Li SS, Wang H, Min J. Binding of different histone marks differentially regulates the activity and specificity of polycomb repressive complex 2 (PRC2). Proc Natl Acad Sci U S A. 2010 Oct 25. PMID:20974918 doi:10.1073/pnas.1008937107
↑ Moody JD, Levy S, Mathieu J, Xing Y, Kim W, Dong C, Tempel W, Robitaille AM, Dang LT, Ferreccio A, Detraux D, Sidhu S, Zhu L, Carter L, Xu C, Valensisi C, Wang Y, Hawkins RD, Min J, Moon RT, Orkin SH, Baker D, Ruohola-Baker H. First critical repressive H3K27me3 marks in embryonic stem cells identified using designed protein inhibitor. Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):10125-10130. doi:, 10.1073/pnas.1706907114. Epub 2017 Sep 1. PMID:28864533 doi:http://dx.doi.org/10.1073/pnas.1706907114

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5wp3"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of EED in complex with EB22==
-<StructureSection load='5wp3' size='340' side='right' caption='[[5wp3]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
+<StructureSection load='5wp3' size='340' side='right'caption='[[5wp3]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5wp3]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Synthetic_construct_sequences Synthetic construct sequences]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WP3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WP3 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5wp3]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WP3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5WP3 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.55&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EED ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5wp3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wp3 OCA], [http://pdbe.org/5wp3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wp3 RCSB], [http://www.ebi.ac.uk/pdbsum/5wp3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wp3 ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5wp3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wp3 OCA], [https://pdbe.org/5wp3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5wp3 RCSB], [https://www.ebi.ac.uk/pdbsum/5wp3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5wp3 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/EED_HUMAN EED_HUMAN]] Polycomb group (PcG) protein. Component of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' and 'Lys-27' of histone H3, leading to transcriptional repression of the affected target gene. Also recognizes 'Lys-26' trimethylated histone H1 with the effect of inhibiting PRC2 complex methyltransferase activity on nucleosomal histone H3 'Lys-27', whereas H3 'Lys-27' recognition has the opposite effect, enabling the propagation of this repressive mark. 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.<ref>PMID:9584199</ref> <ref>PMID:10581039</ref> <ref>PMID:14532106</ref> <ref>PMID:15385962</ref> <ref>PMID:15231737</ref> <ref>PMID:15225548</ref> <ref>PMID:16357870</ref> <ref>PMID:18285464</ref> <ref>PMID:20974918</ref>
+[https://www.uniprot.org/uniprot/EED_HUMAN EED_HUMAN] Polycomb group (PcG) protein. Component of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' and 'Lys-27' of histone H3, leading to transcriptional repression of the affected target gene. Also recognizes 'Lys-26' trimethylated histone H1 with the effect of inhibiting PRC2 complex methyltransferase activity on nucleosomal histone H3 'Lys-27', whereas H3 'Lys-27' recognition has the opposite effect, enabling the propagation of this repressive mark. 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.<ref>PMID:9584199</ref> <ref>PMID:10581039</ref> <ref>PMID:14532106</ref> <ref>PMID:15385962</ref> <ref>PMID:15231737</ref> <ref>PMID:15225548</ref> <ref>PMID:16357870</ref> <ref>PMID:18285464</ref> <ref>PMID:20974918</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 5wp3" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Polycomb complex proteins 3D structures|Polycomb complex proteins 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Synthetic construct sequences]]
+[[Category: Large Structures]]
-[[Category: Arrowsmith, C H]]
+[[Category: Synthetic construct]]
-[[Category: Baker, D]]
+[[Category: Arrowsmith CH]]
-[[Category: Bountra, C]]
+[[Category: Baker D]]
-[[Category: Dong, C]]
+[[Category: Bountra C]]
-[[Category: Edwards, A M]]
+[[Category: Dong C]]
-[[Category: Min, J]]
+[[Category: Edwards AM]]
-[[Category: Moody, J D]]
+[[Category: Min J]]
-[[Category: Structural genomic]]
+[[Category: Moody JD]]
-[[Category: Tempel, W]]
+[[Category: Tempel W]]
-[[Category: Zhu, L]]
+[[Category: Zhu L]]
-[[Category: Gene regulation]]
-[[Category: Sgc]]

5wp3

From Proteopedia

Current revision

Crystal Structure of EED in complex with EB22

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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