7m5u | pdb_00007m5u
Crystal structure of human MPP8 chromodomain in complex with peptidomimetic ligand UNC5246
Structural highlights
FunctionMPP8_HUMAN Involved in transcriptional regulation. Specifically recognizes and binds methylated 'Lys-9' of histone H3 (H3K9me) and promotes DNA methylation by recruiting DNMT3A to target CpG sites; these can be situated within the coding region of the gene. Mediates down-regulation of CDH1 expression.[1] Publication Abstract from PubMedThe interpretation of histone post-translational modifications (PTMs), specifically lysine methylation, by specific classes of "reader" proteins marks an important aspect of epigenetic control of gene expression. Methyl-lysine (Kme) readers often regulate gene expression patterns through the recognition of a specific Kme PTM while participating in or recruiting large protein complexes that contain enzymatic or chromatin remodeling activity. Understanding the composition of these Kme-reader-containing protein complexes can serve to further our understanding of the biological roles of Kme readers, while small molecule chemical tools can be valuable reagents in interrogating novel protein-protein interactions. Here, we describe our efforts to target the chromodomain of M-phase phosphoprotein 8 (MPP8), a member of the human silencing hub (HUSH) complex and a histone 3 lysine 9 trimethyl (H3K9me3) reader that is vital for heterochromatin formation and has specific roles in cancer metastasis. Utilizing a one-bead, one-compound (OBOC) combinatorial screening approach, we identified UNC5246, a peptidomimetic ligand capable of interacting with the MPP8 chromodomain in the context of the HUSH complex. Additionally, a biotinylated derivative of UNC5246 facilitated chemoproteomics studies which revealed hepatoma-derived growth factor-related protein 2 (HRP2) as a novel protein associated with MPP8. HRP2 was further shown to colocalize with MPP8 at the E-cadherin gene locus, suggesting a possible role in cancer cell plasticity. A Peptidomimetic Ligand Targeting the Chromodomain of MPP8 Reveals HRP2's Association with the HUSH Complex.,Waybright JM, Clinkscales SE, Barnash KD, Budziszewski GR, Rectenwald JM, Chiarella AM, Norris-Drouin JL, Cholensky SH, Pearce KH, Herring LE, McGinty RK, Hathaway NA, James LI ACS Chem Biol. 2021 Sep 17;16(9):1721-1736. doi: 10.1021/acschembio.1c00429. Epub , 2021 Aug 20. PMID:34415726[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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