4x3k

From Proteopedia

Crystal structure of chromobox homolog 7 (CBX7) chromodomain with H3K27me3 peptide

PDB ID 4x3k

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Structural highlights

4x3k is a 4 chain structure with sequence from Homo sapiens and Mus musculus. 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_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

Chromobox homolog 7 (CBX7) plays an important role in gene transcription in a wide array of cellular processes, ranging from stem cell self-renewal and differentiation to tumor progression. CBX7 functions through its N-terminal chromodomain (ChD), which recognizes trimethylated lysine 27 of histone 3 (H3K27me3), a conserved epigenetic mark that signifies gene transcriptional repression. In this study, we report the discovery of small molecules that inhibit CBX7ChD binding to H3K27me3. Our crystal structures reveal the binding modes of these molecules that compete against H3K27me3 binding through interactions with key residues in the methyl-lysine binding pocket of CBX7ChD. We further show that a lead compound, MS37452, derepresses transcription of Polycomb repressive complex target gene p16/CDKN2A by displacing CBX7 binding to the INK4A/ARF locus in prostate cancer cells. These small molecules have the potential to be developed into high-potency chemical modulators that target CBX7 functions in gene transcription in different disease pathways.

Small-Molecule Modulators of Methyl-Lysine Binding for the CBX7 Chromodomain.,Ren C, Morohashi K, Plotnikov AN, Jakoncic J, Smith SG, Li J, Zeng L, Rodriguez Y, Stojanoff V, Walsh M, Zhou MM Chem Biol. 2015 Feb 19;22(2):161-8. doi: 10.1016/j.chembiol.2014.11.021. Epub, 2015 Feb 5. PMID:25660273^[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, Morohashi K, Plotnikov AN, Jakoncic J, Smith SG, Li J, Zeng L, Rodriguez Y, Stojanoff V, Walsh M, Zhou MM. Small-Molecule Modulators of Methyl-Lysine Binding for the CBX7 Chromodomain. Chem Biol. 2015 Feb 19;22(2):161-8. doi: 10.1016/j.chembiol.2014.11.021. Epub, 2015 Feb 5. PMID:25660273 doi:http://dx.doi.org/10.1016/j.chembiol.2014.11.021