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5ejw

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Revision as of 07:02, 22 April 2020

Crystal structure of chromobox homolog 7 (CBX7) chromodomain with MS351

Structural highlights

5ejw is a 1 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	Cbx7, D15Ertd417e (LK3 transgenic mice)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[CBX7_MOUSE] 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 histone H3 trimethylated 'Lys-9' (H3K9me3) or at 'Lys-27' (H3K27me3). May possibly also bind trimethylated lysine residues in other proteins (in vitro). Binds non-coding, single-stranded RNA. Regulator of cellular lifespan by maintaining the repression of CDKN2A, but not by inducing telomerase activity.^[1] ^[2]

Publication Abstract from PubMed

The chromobox 7 (CBX7) protein of the polycomb repressive complex 1 (PRC1) functions to repress transcription of tumor suppressor p16 (INK4a) through long noncoding RNA, ANRIL (antisense noncoding RNA in the INK4 locus) directed chromodomain (ChD) binding to trimethylated lysine 27 of histone H3 (H3K27me3), resulting in chromatin compaction at the INK4a/ARF locus. In this study, we report structure-guided discovery of two distinct classes of small-molecule antagonists for the CBX7ChD. Our Class A compounds, a series including analogues of the previously reported MS452, inhibit CBX7ChD/methyl-lysine binding by occupying the H3K27me3 peptide binding site, whereas our Class B compound, the newly discovered MS351, appears to inhibit H3K27me3 binding when CBX7ChD is bound to RNA. Our crystal structure of the CBX7ChD/MS351 complex reveals the molecular details of ligand recognition by the aromatic cage residues that typically engage in methyl-lysine binding. We further demonstrate that MS351 effectively induces transcriptional derepression of CBX7 target genes, including p16 (INK4a) in mouse embryonic stem cells and human prostate cancer PC3 cells. Thus, MS351 represents a new class of ChD antagonists that selectively targets the biologically active form of CBX7 of the PRC1 in long noncoding RNA- and H3K27me3-directed gene transcriptional repression.

Structure-Guided Discovery of Selective Antagonists for the Chromodomain of Polycomb Repressive Protein CBX7.,Ren C, Smith SG, Yap K, Li S, Li J, Mezei M, Rodriguez Y, Vincek A, Aguilo F, Walsh MJ, Zhou MM ACS Med Chem Lett. 2016 Feb 29;7(6):601-5. doi: 10.1021/acsmedchemlett.6b00042., eCollection 2016 Jun 9. PMID:27326334^[3]

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

References

↑ Bernstein E, Duncan EM, Masui O, Gil J, Heard E, Allis CD. Mouse polycomb proteins bind differentially to methylated histone H3 and RNA and are enriched in facultative heterochromatin. Mol Cell Biol. 2006 Apr;26(7):2560-9. PMID:16537902 doi:http://dx.doi.org/10.1128/MCB.26.7.2560-2569.2006
↑ Yap KL, Li S, Munoz-Cabello AM, Raguz S, Zeng L, Mujtaba S, Gil J, Walsh MJ, Zhou MM. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell. 2010 Jun 11;38(5):662-74. PMID:20541999 doi:10.1016/j.molcel.2010.03.021
↑ Ren C, Smith SG, Yap K, Li S, Li J, Mezei M, Rodriguez Y, Vincek A, Aguilo F, Walsh MJ, Zhou MM. Structure-Guided Discovery of Selective Antagonists for the Chromodomain of Polycomb Repressive Protein CBX7. ACS Med Chem Lett. 2016 Feb 29;7(6):601-5. doi: 10.1021/acsmedchemlett.6b00042., eCollection 2016 Jun 9. PMID:27326334 doi:http://dx.doi.org/10.1021/acsmedchemlett.6b00042

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 1: / Line 1: @@
 ==Crystal structure of chromobox homolog 7 (CBX7) chromodomain with MS351==
-<StructureSection load='5ejw' size='340' side='right' caption='[[5ejw]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
+<StructureSection load='5ejw' size='340' side='right'caption='[[5ejw]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5ejw]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EJW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5EJW FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5ejw]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EJW OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5EJW FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5PZ:(1~{R})-2-[2-AZANYLIDENE-3-[(2-METHYLPHENYL)METHYL]BENZIMIDAZOL-1-YL]-1-(3,4-DICHLOROPHENYL)ETHANOL'>5PZ</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5PZ:(1~{R})-2-[2-AZANYLIDENE-3-[(2-METHYLPHENYL)METHYL]BENZIMIDAZOL-1-YL]-1-(3,4-DICHLOROPHENYL)ETHANOL'>5PZ</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=5ejw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ejw OCA], [http://pdbe.org/5ejw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ejw RCSB], [http://www.ebi.ac.uk/pdbsum/5ejw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ejw ProSAT]</span></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Cbx7, D15Ertd417e ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5ejw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ejw OCA], [http://pdbe.org/5ejw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ejw RCSB], [http://www.ebi.ac.uk/pdbsum/5ejw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ejw ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
+[[Category: Lk3 transgenic mice]]
 [[Category: Ren, C]]
 [[Category: Zhou, M M]]

5ejw

From Proteopedia

Revision as of 07:02, 22 April 2020

Crystal structure of chromobox homolog 7 (CBX7) chromodomain with MS351

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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