4UP5

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

Summary for 4UP5

• Entry DOI: 10.2210/pdb4up5/pdb
• Related: 4UP0
• Descriptor: PYGOPUS HOMOLOG 2, B-CELL CLL/LYMPHOMA 9-LIKE PROTEIN, ZINC ION, 6-methoxy-1,3-benzothiazol-2-amine, ... (4 entities in total)
• Functional Keywords: transcription, pygo, wnt signalling, histone h3, fragment screening
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Nucleus : Q86UU0
• Total number of polymer chains: 1
• Total formula weight: 10848.72

Authors

Miller, T.C.R.,Fiedler, M.,Rutherford, T.J.,Birchall, K.,Chugh, J.,Bienz, M. (deposition date: 2014-06-12, release date: 2014-11-05, Last modification date: 2024-01-10)

Primary citation

Miller, T.C.R.,Rutherford, T.J.,Birchall, K.,Chugh, J.,Fiedler, M.,Bienz, M.
Competitive Binding of a Benzimidazole to the Histone-Binding Pocket of the Pygo Phd Finger.
Acs Chem.Biol., 9:2864-, 2014

PubMed Abstract: The Pygo-BCL9 complex is a chromatin reader, facilitating β-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.

PubMed: 25323450
DOI: 10.1021/CB500585S

Experimental method

X-RAY DIFFRACTION (1.65 Å)