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  • Conformational dynamics of ...
    Houliston, R. Scott; Lemak, Alexander; Iqbal, Aman; Ivanochko, Danton; Duan, Shili; Kaustov, Lilia; Ong, Michelle S.; Fan, Lixin; Senisterra, Guillermo; Brown, Peter J.; Wang, Yun-Xing; Arrowsmith, Cheryl H.

    Journal of biological chemistry/˜The œJournal of biological chemistry, 12/2017, Letnik: 292, Številka: 51
    Journal Article

    UHRF1 is a key mediator of inheritance of epigenetic DNA methylation patterns during cell division and is a putative target for cancer therapy. Recent studies indicate that interdomain interactions critically influence UHRF1’s chromatin-binding properties, including allosteric regulation of its histone binding. Here, using an integrative approach that combines small angle X-ray scattering, NMR spectroscopy, and molecular dynamics simulations, we characterized the dynamics of the tandem tudor domain–plant homeodomain (TTD–PHD) histone reader module, including its 20-residue interdomain linker. We found that the apo TTD–PHD module in solution comprises a dynamic ensemble of conformers, approximately half of which are compact conformations, with the linker lying in the TTD peptide–binding groove. These compact conformations are amenable to cooperative, high-affinity histone binding. In the remaining conformations, the linker position was in flux, and the reader adopted both extended and compact states. Using a small-molecule fragment screening approach, we identified a compound, 4-benzylpiperidine-1-carboximidamide, that binds to the TTD groove, competes with linker binding, and promotes open TTD–PHD conformations that are less efficient at H3K9me3 binding. Our work reveals a mechanism by which the dynamic TTD–PHD module can be allosterically targeted with small molecules to modulate its histone reader function for therapeutic or experimental purposes.