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| | ==Chromodomain antagonists that target the polycomb-group methyllysine reader protein Chromobox homolog 7 (CBX7)== | | ==Chromodomain antagonists that target the polycomb-group methyllysine reader protein Chromobox homolog 7 (CBX7)== |
| - | <StructureSection load='4mn3' size='340' side='right' caption='[[4mn3]], [[Resolution|resolution]] 1.54Å' scene=''> | + | <StructureSection load='4mn3' size='340' side='right'caption='[[4mn3]], [[Resolution|resolution]] 1.54Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4mn3]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MN3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MN3 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4mn3]] 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=4MN3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MN3 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=P33:3,6,9,12,15,18-HEXAOXAICOSANE-1,20-DIOL'>P33</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=M3L:N-TRIMETHYLLYSINE'>M3L</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=P33:3,6,9,12,15,18-HEXAOXAICOSANE-1,20-DIOL'>P33</scene></td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=M3L:N-TRIMETHYLLYSINE'>M3L</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</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=4mn3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mn3 OCA], [https://pdbe.org/4mn3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mn3 RCSB], [https://www.ebi.ac.uk/pdbsum/4mn3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mn3 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CBX7 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4mn3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mn3 OCA], [http://pdbe.org/4mn3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4mn3 RCSB], [http://www.ebi.ac.uk/pdbsum/4mn3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4mn3 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CBX7_HUMAN CBX7_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. Promotes histone H3 trimethylation at 'Lys-9' (H3K9me3). Binds to trimethylated lysine residues in histones, and possibly also other proteins. Regulator of cellular lifespan by maintaining the repression of CDKN2A, but not by inducing telomerase activity.<ref>PMID:19636380</ref> <ref>PMID:21060834</ref> <ref>PMID:21282530</ref> <ref>PMID:21047797</ref> | + | [https://www.uniprot.org/uniprot/CBX7_HUMAN CBX7_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. Promotes histone H3 trimethylation at 'Lys-9' (H3K9me3). Binds to trimethylated lysine residues in histones, and possibly also other proteins. Regulator of cellular lifespan by maintaining the repression of CDKN2A, but not by inducing telomerase activity.<ref>PMID:19636380</ref> <ref>PMID:21060834</ref> <ref>PMID:21282530</ref> <ref>PMID:21047797</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Boulanger, M J]] | + | [[Category: Large Structures]] |
| - | [[Category: Chakravarthi, S]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Daze, K]] | + | [[Category: Boulanger MJ]] |
| - | [[Category: Dev, A]] | + | [[Category: Chakravarthi S]] |
| - | [[Category: Douglas, S]] | + | [[Category: Daze K]] |
| - | [[Category: Heller, M]] | + | [[Category: Dev A]] |
| - | [[Category: Hof, F]] | + | [[Category: Douglas S]] |
| - | [[Category: Peng, F]] | + | [[Category: Heller M]] |
| - | [[Category: Quon, T]] | + | [[Category: Hof F]] |
| - | [[Category: Wulff, J]] | + | [[Category: Peng F]] |
| - | [[Category: Chromobox domain 7]]
| + | [[Category: Quon T]] |
| - | [[Category: Transcription regulator]]
| + | [[Category: Wulff J]] |
| Structural highlights
4mn3 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.
| | Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
CBX7_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. Promotes histone H3 trimethylation at 'Lys-9' (H3K9me3). Binds to trimethylated lysine residues in histones, and possibly also other proteins. Regulator of cellular lifespan by maintaining the repression of CDKN2A, but not by inducing telomerase activity.[1] [2] [3] [4]
Publication Abstract from PubMed
We report here a peptide-driven approach to create first inhibitors of the chromobox homolog 7 (CBX7), a methyllysine reader protein. CBX7 uses its chromodomain to bind histone 3, lysine 27 trimethylated (H3K27me3), and this recognition event is implicated in silencing multiple tumor suppressors. Small trimethyllysine containing peptides were used as the basic scaffold from which potent ligands for disruption of CBX7-H3K27me3 complex were developed. Potency of ligands was determined by fluorescence polarization and/or isothermal titration calorimetry. Binding of one ligand was characterized in detail using 2D NMR and X-ray crystallography, revealing a structural motif unique among human CBX proteins. Inhibitors with a approximately 200 nM potency for CBX7 binding and 10-fold/400-fold selectivity over related CBX8/CBX1 proteins were identified. These are the first reported inhibitors of any chromodomain.
Chromodomain Antagonists That Target the Polycomb-Group Methyllysine Reader Protein Chromobox Homolog 7 (CBX7).,Simhadri C, Daze KD, Douglas SF, Quon TT, Dev A, Gignac MC, Peng F, Heller M, Boulanger MJ, Wulff JE, Hof F J Med Chem. 2014 Mar 26. PMID:24625057[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Maertens GN, El Messaoudi-Aubert S, Racek T, Stock JK, Nicholls J, Rodriguez-Niedenfuhr M, Gil J, Peters G. Several distinct polycomb complexes regulate and co-localize on the INK4a tumor suppressor locus. PLoS One. 2009 Jul 28;4(7):e6380. doi: 10.1371/journal.pone.0006380. PMID:19636380 doi:http://dx.doi.org/10.1371/journal.pone.0006380
- ↑ Li Q, Wang X, Lu Z, Zhang B, Guan Z, Liu Z, Zhong Q, Gu L, Zhou J, Zhu B, Ji J, Deng D. Polycomb CBX7 directly controls trimethylation of histone H3 at lysine 9 at the p16 locus. PLoS One. 2010 Oct 29;5(10):e13732. doi: 10.1371/journal.pone.0013732. PMID:21060834 doi:http://dx.doi.org/10.1371/journal.pone.0013732
- ↑ 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
- ↑ Kaustov L, Ouyang H, Amaya M, Lemak A, Nady N, Duan S, Wasney GA, Li Z, Vedadi M, Schapira M, Min J, Arrowsmith CH. Recognition and specificity determinants of the human cbx chromodomains. J Biol Chem. 2011 Jan 7;286(1):521-9. Epub 2010 Nov 3. PMID:21047797 doi:10.1074/jbc.M110.191411
- ↑ Simhadri C, Daze KD, Douglas SF, Quon TT, Dev A, Gignac MC, Peng F, Heller M, Boulanger MJ, Wulff JE, Hof F. Chromodomain Antagonists That Target the Polycomb-Group Methyllysine Reader Protein Chromobox Homolog 7 (CBX7). J Med Chem. 2014 Mar 26. PMID:24625057 doi:http://dx.doi.org/10.1021/jm401487x
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