4TTE

Crystal structure of ATAD2A bromodomain complexed with methyl 3-amino-5-(3,5-dimethyl-1,2-oxazol-4-yl)benzoate

4TTE の概要

• エントリーDOI: 10.2210/pdb4tte/pdb
• 関連するPDBエントリー: 4TT2 4TT4 4TT6 4TU4 4TU6
• 分子名称: ATPase family AAA domain-containing protein 2, SULFATE ION, CHLORIDE ION, ... (6 entities in total)
• 機能のキーワード: atad2 bromodomain inhibitor complex, gene regulation
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : Q6PL18
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 15923.39

構造登録者

Poncet-Montange, G.,Zhan, Y.,Bardenhagen, J.,Petrocchi, A.,Leo, E.,Shi, X.,Lee, G.,Leonard, P.,Geck Do, M.,Cardozo, M.,Palmer, W.,Andersen, J.,Jones, P.,Ladbury, J. (登録日: 2014-06-20, 公開日: 2014-12-24, 最終更新日: 2023-09-27)

主引用文献

Poncet-Montange, G.,Zhan, Y.,Bardenhagen, J.P.,Petrocchi, A.,Leo, E.,Shi, X.,Lee, G.R.,Leonard, P.G.,Geck Do, M.K.,Cardozo, M.G.,Andersen, J.N.,Palmer, W.S.,Jones, P.,Ladbury, J.E.
Observed bromodomain flexibility reveals histone peptide- and small molecule ligand-compatible forms of ATAD2.
Biochem.J., 466:337-346, 2015

PubMed Abstract: Preventing histone recognition by bromodomains emerges as an attractive therapeutic approach in cancer. Overexpression of ATAD2 (ATPase family AAA domain-containing 2 isoform A) in cancer cells is associated with poor prognosis making the bromodomain of ATAD2 a promising epigenetic therapeutic target. In the development of an in vitro assay and identification of small molecule ligands, we conducted structure-guided studies which revealed a conformationally flexible ATAD2 bromodomain. Structural studies on apo-, peptide-and small molecule-ATAD2 complexes (by co-crystallization) revealed that the bromodomain adopts a 'closed', histone-compatible conformation and a more 'open' ligand-compatible conformation of the binding site respectively. An unexpected conformational change of the conserved asparagine residue plays an important role in driving the peptide-binding conformation remodelling. We also identified dimethylisoxazole-containing ligands as ATAD2 binders which aided in the validation of the in vitro screen and in the analysis of these conformational studies.

PubMed: 25486442
DOI: 10.1042/BJ20140933

実験手法

X-RAY DIFFRACTION (1.8 Å)