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Structural Analysis of Small-Molecule Binding to the BAZ2A and BAZ2B Bromodomains


Dalle Vedove, Andrea; Spiliotopoulos, Dimitrios; D'Agostino, Vito G; Marchand, Jean-Rémy; Unzue, Andrea; Nevado, Cristina; Lolli, Graziano; Caflisch, Amedeo (2018). Structural Analysis of Small-Molecule Binding to the BAZ2A and BAZ2B Bromodomains. ChemMedChem, 13(14):1479-1487.

Abstract

The bromodomain-containing protein BAZ2A is a validated target in prostate cancer research, whereas the function of its paralogue BAZ2B is still undefined. The bromodomains of BAZ2A and BAZ2B have a similar binding site for their natural ligand, the acetylated lysine side chain. Here, we present an analysis of the binding modes of eight compounds belonging to three distinct chemical classes. For all compounds, the moiety mimicking the natural ligand engages in essentially identical interactions in the BAZ2A and BAZ2B bromodomains. In contrast, the rest of the molecule is partially solvent-exposed and adopts different orientations with different interactions in the two bromodomains. Some of these differences could be exploited for designing inhibitors with selectivity within the BAZ2 bromodomain subfamily.

Abstract

The bromodomain-containing protein BAZ2A is a validated target in prostate cancer research, whereas the function of its paralogue BAZ2B is still undefined. The bromodomains of BAZ2A and BAZ2B have a similar binding site for their natural ligand, the acetylated lysine side chain. Here, we present an analysis of the binding modes of eight compounds belonging to three distinct chemical classes. For all compounds, the moiety mimicking the natural ligand engages in essentially identical interactions in the BAZ2A and BAZ2B bromodomains. In contrast, the rest of the molecule is partially solvent-exposed and adopts different orientations with different interactions in the two bromodomains. Some of these differences could be exploited for designing inhibitors with selectivity within the BAZ2 bromodomain subfamily.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry

07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:18 July 2018
Deposited On:04 Sep 2018 13:30
Last Modified:26 Feb 2019 08:08
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1860-7179
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1002/cmdc.201800234
PubMed ID:29770599

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