Structural highlights
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Miller TC, Rutherford TJ, 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. 2014 Oct 24. PMID:25323450 doi:http://dx.doi.org/10.1021/cb500585s
