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)

    Research output: Contribution to journalArticle

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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

    Fingerprint

    Epigenomics
    Histones
    Magnetic Resonance Spectroscopy
    Binding Sites
    Nuclear magnetic resonance
    Peptides
    Molecules
    Water
    Chemical shift
    Nuclear magnetic resonance spectroscopy
    Pharmaceutical Preparations
    Experiments
    Pharmaceutical Research

    Keywords

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

    Cite this

    Ferguson, F. M., Dias, D. M., Rodrigues, J. P. G. L. M., Wienk, H., Boelens, R., Bonvin, A. M. J. J., ... 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
    Ferguson, Fleur M. ; Dias, David M. ; Rodrigues, João P. G. L. M. ; Wienk, Hans ; Boelens, Rolf ; Bonvin, Alexandre M. J. J. ; Abell, Chris ; Ciulli, Alessio. / Binding hotspots of BAZ2B bromodomain : histone interaction revealed by solution NMR driven docking. In: Biochemistry. 2014 ; Vol. 53, No. 42. pp. 6706-6716.
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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.",
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    Ferguson, FM, Dias, DM, Rodrigues, JPGLM, Wienk, H, Boelens, R, Bonvin, AMJJ, Abell, C & Ciulli, A 2014, 'Binding hotspots of BAZ2B bromodomain: histone interaction revealed by solution NMR driven docking', Biochemistry, vol. 53, no. 42, pp. 6706-6716. https://doi.org/10.1021/bi500909d

    Binding hotspots of BAZ2B bromodomain : histone interaction revealed by solution NMR driven docking. / Ferguson, Fleur M.; Dias, David M.; Rodrigues, João P. G. L. M.; Wienk, Hans; Boelens, Rolf; Bonvin, Alexandre M. J. J.; Abell, Chris; Ciulli, Alessio (Lead / Corresponding author).

    In: Biochemistry, Vol. 53, No. 42, 28.10.2014, p. 6706-6716.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Binding hotspots of BAZ2B bromodomain

    T2 - histone interaction revealed by solution NMR driven docking

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    AU - Dias, David M.

    AU - Rodrigues, João P. G. L. M.

    AU - Wienk, Hans

    AU - Boelens, Rolf

    AU - Bonvin, Alexandre M. J. J.

    AU - Abell, Chris

    AU - Ciulli, Alessio

    PY - 2014/10/28

    Y1 - 2014/10/28

    N2 - 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.

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    AN - SCOPUS:84908278490

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    Ferguson FM, Dias DM, Rodrigues JPGLM, Wienk H, Boelens R, Bonvin AMJJ et al. Binding hotspots of BAZ2B bromodomain: histone interaction revealed by solution NMR driven docking. Biochemistry. 2014 Oct 28;53(42):6706-6716. https://doi.org/10.1021/bi500909d