4UP5: Crystal Structure Of The Pygo2 Phd Finger In Complex With The B9l Hd1 Domain And A Chemical Fragment

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.
PDB ID: 4UP5Download
MMDB ID: 124556
PDB Deposition Date: 2014/6/12
Updated in MMDB: 2014/11
Experimental Method:
x-ray diffraction
Resolution: 1.65  Å
Source Organism:
Similar Structures:
Biological Unit for 4UP5: monomeric; determined by author and by software (PISA)
Molecular Components in 4UP5
Label Count Molecule
Protein (1 molecule)
Pygopus Homolog 2, B-cell Cll/lymphoma 9-like Protein
Molecule annotation
Chemicals (3 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB