5epk

From Proteopedia

(Difference between revisions)

Current revision

Crystal Structure of chromodomain of CBX2 in complex with inhibitor UNC3866

Structural highlights

5epk is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.8Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CBX2_HUMAN Defects in CBX2 are the cause of 46,XY sex reversal type 5 (SRXY5) [MIM:613080. It is a disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females.^[1]

Function

CBX2_HUMAN Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility. Involved in sexual development, acting as activator of NR5A1 expression.^[2] ^[3]

Publication Abstract from PubMed

We report the design and characterization of UNC3866, a potent antagonist of the methyllysine (Kme) reading function of the Polycomb CBX and CDY families of chromodomains. Polycomb CBX proteins regulate gene expression by targeting Polycomb repressive complex 1 (PRC1) to sites of H3K27me3 via their chromodomains. UNC3866 binds the chromodomains of CBX4 and CBX7 most potently, with a Kd of approximately 100 nM for each, and is 6- to 18-fold selective as compared to seven other CBX and CDY chromodomains while being highly selective over >250 other protein targets. X-ray crystallography revealed that UNC3866's interactions with the CBX chromodomains closely mimic those of the methylated H3 tail. UNC4195, a biotinylated derivative of UNC3866, was used to demonstrate that UNC3866 engages intact PRC1 and that EED incorporation into PRC1 is isoform dependent in PC3 prostate cancer cells. Finally, UNC3866 inhibits PC3 cell proliferation, consistent with the known ability of CBX7 overexpression to confer a growth advantage, whereas UNC4219, a methylated negative control compound, has negligible effects.

A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1.,Stuckey JI, Dickson BM, Cheng N, Liu Y, Norris JL, Cholensky SH, Tempel W, Qin S, Huber KG, Sagum C, Black K, Li F, Huang XP, Roth BL, Baughman BM, Senisterra G, Pattenden SG, Vedadi M, Brown PJ, Bedford MT, Min J, Arrowsmith CH, James LI, Frye SV Nat Chem Biol. 2016 Mar;12(3):180-7. doi: 10.1038/nchembio.2007. Epub 2016 Jan, 25. PMID:26807715^[4]

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

References

↑ Biason-Lauber A, Konrad D, Meyer M, DeBeaufort C, Schoenle EJ. Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene. Am J Hum Genet. 2009 May;84(5):658-63. doi: 10.1016/j.ajhg.2009.03.016. Epub 2009, Apr 9. PMID:19361780 doi:10.1016/j.ajhg.2009.03.016
↑ Biason-Lauber A, Konrad D, Meyer M, DeBeaufort C, Schoenle EJ. Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene. Am J Hum Genet. 2009 May;84(5):658-63. doi: 10.1016/j.ajhg.2009.03.016. Epub 2009, Apr 9. PMID:19361780 doi:10.1016/j.ajhg.2009.03.016
↑ Vandamme J, Volkel P, Rosnoblet C, Le Faou P, Angrand PO. Interaction proteomics analysis of polycomb proteins defines distinct PRC1 complexes in mammalian cells. Mol Cell Proteomics. 2011 Apr;10(4):M110.002642. doi: 10.1074/mcp.M110.002642., Epub 2011 Jan 31. PMID:21282530 doi:10.1074/mcp.M110.002642
↑ Stuckey JI, Dickson BM, Cheng N, Liu Y, Norris JL, Cholensky SH, Tempel W, Qin S, Huber KG, Sagum C, Black K, Li F, Huang XP, Roth BL, Baughman BM, Senisterra G, Pattenden SG, Vedadi M, Brown PJ, Bedford MT, Min J, Arrowsmith CH, James LI, Frye SV. A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1. Nat Chem Biol. 2016 Mar;12(3):180-7. doi: 10.1038/nchembio.2007. Epub 2016 Jan, 25. PMID:26807715 doi:http://dx.doi.org/10.1038/nchembio.2007

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 5: / Line 5: @@
 <table><tr><td colspan='2'>[[5epk]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EPK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EPK FirstGlance]. <br>
 </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</td></tr>
-<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5R0:4-~{TERT}-BUTYLBENZOIC+ACID'>5R0</scene>, <scene name='pdbligand=5R5:METHYL+(2~{S})-2-AZANYL-3-OXIDANYL-PROPANOATE'>5R5</scene>, <scene name='pdbligand=ELY:N~6~,N~6~-DIETHYL-L-LYSINE'>ELY</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5R0:4-~{TERT}-BUTYLBENZOIC+ACID'>5R0</scene>, <scene name='pdbligand=5R5:METHYL+(2~{S})-2-AZANYL-3-OXIDANYL-PROPANOATE'>5R5</scene>, <scene name='pdbligand=ELY:N~6~,N~6~-DIETHYL-L-LYSINE'>ELY</scene></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=5epk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5epk OCA], [https://pdbe.org/5epk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5epk RCSB], [https://www.ebi.ac.uk/pdbsum/5epk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5epk ProSAT]</span></td></tr>
 </table>

5epk

From Proteopedia

Current revision

Crystal Structure of chromodomain of CBX2 in complex with inhibitor UNC3866

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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