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Using In Vitro and In-cell SHAPE to Investigate Small Molecule Induced Pre-mRNA Structural Changes
Published on: January 30, 2019
Structural Analysis of Small-Molecule Binding to the BAZ2A and BAZ2B Bromodomains
Andrea Dalle Vedove1, Dimitrios Spiliotopoulos2, Vito G D'Agostino1
1Centre for Integrative Biology, University of Trento, via Sommarive 9, 38123, Povo-Trento, Italy.
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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