7M5U

Crystal structure of human MPP8 chromodomain in complex with peptidomimetic ligand UNC5246

Summary for 7M5U

• Entry DOI: 10.2210/pdb7m5u/pdb
• Descriptor: M-phase phosphoprotein 8, UNC5246 (3 entities in total)
• Functional Keywords: chromodomain, peptidomimetic, chromatin, gene regulation
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 8138.34

Authors

Budziszewski, G.R.,McGinty, R.K.,Waybright, J.M.,Norris, J.L.,James, L.I. (deposition date: 2021-03-24, release date: 2021-09-01, Last modification date: 2023-11-15)

Primary citation

Waybright, J.M.,Clinkscales, S.E.,Barnash, K.D.,Budziszewski, G.R.,Rectenwald, J.M.,Chiarella, A.M.,Norris-Drouin, J.L.,Cholensky, S.H.,Pearce, K.H.,Herring, L.E.,McGinty, R.K.,Hathaway, N.A.,James, L.I.
A Peptidomimetic Ligand Targeting the Chromodomain of MPP8 Reveals HRP2's Association with the HUSH Complex.
Acs Chem.Biol., 16:1721-1736, 2021

PubMed Abstract: The 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 gene locus, suggesting a possible role in cancer cell plasticity.

PubMed: 34415726
DOI: 10.1021/acschembio.1c00429

Experimental method

X-RAY DIFFRACTION (2.02 Å)