4up5

Crystal structure of the Pygo2 PHD finger in complex with the B9L HD1 domain and a chemical fragment

spinqualitylabelsall models 4up5, resolution 1.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4up5 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 94W, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PYGO2_HUMAN Involved in signal transduction through the Wnt pathway.BCL9L_HUMAN Transcriptional regulator that acts as an activator. Promotes beta-catenin transcriptional activity. Plays a role in tumorigenesis. Enhances the neoplastic transforming activity of CTNNB1 (By similarity). Publication Abstract from PubMed The Pygo-BCL9 complex is a chromatin reader, facilitating beta-catenin-mediated oncogenesis, and is thus emerging as a potential therapeutic target for cancer. Its function relies on two ligand-binding surfaces of Pygo's PHD finger that anchor the histone H3 tail methylated at lysine 4 (H3K4me) with assistance from the BCL9 HD1 domain. Here, we report the first use of fragment-based screening by NMR to identify small molecules that block protein-protein interactions by a PHD finger. This led to the discovery of a set of benzothiazoles that bind to a cleft emanating from the PHD-HD1 interface, as defined by X-ray crystallography. Furthermore, we discovered a benzimidazole that docks into the H3K4me specificity pocket and displaces the native H3K4me peptide from the PHD finger. Our study demonstrates the ligandability of the Pygo-BCL9 complex and uncovers a privileged scaffold as a template for future development of lead inhibitors of oncogenesis. Competitive Binding of a Benzimidazole to the Histone-Binding Pocket of the Pygo PHD Finger.,Miller TC, Rutherford TJ, Birchall K, Chugh J, Fiedler M, Bienz M ACS Chem Biol. 2014 Oct 24. PMID:25323450 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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