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J Biol Chem. 2017 Dec 22;292(51):20947-20959. doi: 10.1074/jbc.M117.799700. Epub 2017 Oct 26.

Conformational dynamics of the TTD-PHD histone reader module of the UHRF1 epigenetic regulator reveals multiple histone-binding states, allosteric regulation, and druggability.

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From the Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
the Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
the Small-Angle X-ray Scattering Core Facility, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, Maryland 21702, and.
the NCI, National Institutes of Health, Frederick, Maryland 21702.
From the Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada,


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.


drug screening; epigenetics; molecular dynamics; molecular modeling; nuclear magnetic resonance (NMR); protein dynamic

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