PDBsum entry 4up0

Transcription

PDB id: 4up0

Contents

Protein chain

85 a.a.

Ligands

ALA-ARG-THR-MLY-GLN-THR

Metals

_ZN ×2

Waters ×94

References listed in PDB file

Key reference

• Title: Competitive binding of a benzimidazole to the histone-Binding pocket of the pygo phd finger.
• Authors: T.C.Miller, T.J.Rutherford, K.Birchall, J.Chugh, M.Fiedler, M.Bienz.
• Ref.: Acs Chem Biol, 2014, 9, 2864-2874. [DOI no: 10.1021/cb500585s]
• PubMed id: 25323450

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.