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| Hauptseite > Publikationsdatenbank > Structural and thermodynamic characterization of the binding of isoliquiritigenin to the first bromodomain of BRD4 |
| Hauptseite > Publikationsdatenbank > Structural and thermodynamic characterization of the binding of isoliquiritigenin to the first bromodomain of BRD4 |
| Journal Article | FZJ-2020-00324 |
; ; ; ; ;
2019
Wiley-Blackwell
Oxford [u.a.]
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Please use a persistent id in citations: doi:10.1111/febs.14736
Abstract: Bromodomain-containing protein 4 (BRD4) recognizes the acetylated lysineof histone H4 via its bromodomains, leading to the recruitment of positivetranscription elongation factor b. Small molecules that inhibit BRD4 havepotential as anticancer agents by leading to the downregulation of specificoncogenes. Using X-ray crystallographic screening, we identified the BRD4inhibitory activity of isoliquiritigenin (ISL), a natural chalcone found inlicorice. Structural analysis revealed that ISL bound to BRD4 with a novelbinding mode and squeezed out one of the six conserved water moleculesthat form a strong hydrogen bond network. The thermodynamic analysisrevealed that the binding of ISL is enthalpy driven, suggesting that stronghydrogen bonds would compensate for the desolvation penalty. Neutronprotein crystallography further suggested that the favorable bindingenthalpy originates from the stabilization and optimization of the hydrogenbond network of the conserved water molecules. Here, we describe the noveltyand potential of ISL as a template for new BRD4 inhibitors.
Keyword(s): Health and Life (1st) ; Biology (2nd)
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