4UP5

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

4UP5 の概要

• エントリーDOI: 10.2210/pdb4up5/pdb
• 関連するPDBエントリー: 4UP0
• 分子名称: PYGOPUS HOMOLOG 2, B-CELL CLL/LYMPHOMA 9-LIKE PROTEIN, ZINC ION, 6-methoxy-1,3-benzothiazol-2-amine, ... (4 entities in total)
• 機能のキーワード: transcription, pygo, wnt signalling, histone h3, fragment screening
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Nucleus : Q86UU0
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 10848.72

構造登録者

Miller, T.C.R.,Fiedler, M.,Rutherford, T.J.,Birchall, K.,Chugh, J.,Bienz, M. (登録日: 2014-06-12, 公開日: 2014-11-05, 最終更新日: 2024-01-10)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.65 Å)