Binding hotspots of BAZ2B bromodomain: histone interaction revealed by solution NMR driven docking

Fleur M. Ferguson, David M. Dias, João P. G. L. M. Rodrigues, Hans Wienk, Rolf Boelens, Alexandre M. J. J. Bonvin, Chris Abell, Alessio Ciulli (Lead / Corresponding author)

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    Abstract

    Bromodomains are epigenetic reader domains, which have come under increasing scrutiny both from academic and pharmaceutical research groups. Effective targeting of the BAZ2B bromodomain by small molecule inhibitors has been recently reported, but no structural information is yet available on the interaction with its natural binding partner, acetylated histone H3K14ac. We have assigned the BAZ2B bromodomain and studied its interaction with H3K14ac acetylated peptides by NMR spectroscopy using both chemical shift perturbation (CSP) data and clean chemical exchange (CLEANEX-PM) NMR experiments. The latter was used to characterize water molecules known to play an important role in mediating interactions. Besides the anticipated Kac binding site, we consistently found the bromodomain BC loop as hotspots for the interaction. This information was used to create a data-driven model for the complex using HADDOCK. Our findings provide both structure and dynamics characterization that will be useful in the quest for potent and selective inhibitors to probe the function of the BAZ2B bromodomain.

    Original languageEnglish
    Pages (from-to)6706-6716
    Number of pages11
    JournalBiochemistry
    Volume53
    Issue number42
    DOIs
    Publication statusPublished - 28 Oct 2014

    Keywords

    • Acetylation
    • Histones
    • Humans
    • Molecular Docking Simulation
    • Nuclear Magnetic Resonance, Biomolecular
    • Nuclear Proteins
    • Peptides
    • Protein Binding
    • Protein Structure, Tertiary
    • Solutions

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    Cite this

    Ferguson, F. M., Dias, D. M., Rodrigues, J. P. G. L. M., Wienk, H., Boelens, R., Bonvin, A. M. J. J., Abell, C., & Ciulli, A. (2014). Binding hotspots of BAZ2B bromodomain: histone interaction revealed by solution NMR driven docking. Biochemistry, 53(42), 6706-6716. https://doi.org/10.1021/bi500909d