Structure-Guided Discovery of Selective Antagonists for the Chromodomain of Polycomb Repressive Protein CBX7
journal contributionposted on 29.02.2016, 00:00 by Chunyan Ren, Steven G. Smith, Kyoko Yap, SiDe Li, Jiaojie Li, Mihaly Mezei, Adam Vincek, Francesca Aguilo, Martin J. Walsh, Ming-Ming Zhou
The chromobox 7 (CBX7) protein of the polycomb repressive complex 1 (PRC1) functions to repress transcription of tumor suppressor p16INK4a 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 p16INK4a 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.
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antisense noncoding RNAPRCprostate cancer PC 3 cellsnoncoding RNACBX 7ChDINK 4a locustumor suppressor p 16 INK 4ap 16 INK 4aCBX 7 target genesANRILH 3K bindingH 3K gene transcriptional repressiontrimethylated lysine 27Class B compoundCBX 7ChD bindingH 3K peptide binding siteMS 351INK 4 locusPolycomb Repressive Protein CBX 7histone H 3