4TU4

Crystal structure of ATAD2A bromodomain complexed with 3-(3,5-dimethyl-1,2-oxazol-4-yl)-5-[(phenylsulfonyl)amino]benzoicacid

Summary for 4TU4

• Entry DOI: 10.2210/pdb4tu4/pdb
• Related: 4TT2 4TT4 4TT6 4TTE 4TU6
• Descriptor: ATPase family AAA domain-containing protein 2, SULFATE ION, GLYCEROL, ... (7 entities in total)
• Functional Keywords: atad2a - bromodomain- inhibitor complex, gene regulation
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : Q6PL18
• Total number of polymer chains: 1
• Total formula weight: 16219.75

Authors

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. (deposition date: 2014-06-23, release date: 2014-12-24, Last modification date: 2023-09-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.73 Å)