Poncet-Montange, G, Zhan, Y, Bardenhagen, JP et al. (11 more authors) (2015) Observed bromodomain flexibility reveals histone peptide- and small molecule ligand-compatible forms of ATAD2. Biochemical Journal, 466 (2). 337 - 346. ISSN 0264-6021
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Keywords: | ATPase family AAA domain-containing 2 isoform A (ATAD2) bromodomain, cancer target, epigenetics, protein flexibility, Histone 4 Lys5 acetyl peptide (H4K5ac) |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 29 Sep 2015 15:21 |
Last Modified: | 31 Oct 2015 10:53 |
Published Version: | http://dx.doi.org/10.1042/BJ20140933 |
Status: | Published |
Publisher: | Portland Press |
Identification Number: | 10.1042/BJ20140933 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:86704 |