title: Molecular Insights into Inhibition of the Methylated Histone-Plant Homeodomain Complexes by Calixarenes.
abstract: Plant homeodomain (PHD) finger-containing proteins are implicated in fundamental biological processes, including transcriptional activation and repression, DNA damage repair, cell differentiation, and survival. The PHD finger functions as an epigenetic reader that binds to posttranslationally modified or unmodified histone H3 tails, recruiting catalytic writers and erasers and other components of the epigenetic machinery to chromatin. Despite the critical role of the histone-PHD interaction in normal and pathological processes, selective inhibitors of this association have not been well developed. Here we demonstrate that macrocyclic calixarenes can disrupt binding of PHD fingers to methylated lysine 4 of histone H3 in vitro and in vivo. The inhibitory activity relies on differences in binding affinities of the PHD fingers for H3K4me and the methylation state of the histone ligand, whereas the composition of the aromatic H3K4me-binding site of the PHD fingers appears to have no effect. Our approach provides a novel tool for studying the biological roles of methyllysine readers in epigenetic signaling.
authors.affiliation: From the Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado 80045.
authors.forename: Muzaffar
authors.initials: M
authors.lastname: Ali
authors.affiliation: the Department of Chemistry, University of Victoria, Victoria, British Columbia V8W 3V6, Canada.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Daze
authors.affiliation: the Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Strongin
authors.affiliation: the Center for Epigenetics, Van Andel Research Institute, Grand Rapids, Michigan 49503.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Rothbart
authors.affiliation: the Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109.
authors.forename: Hector
authors.initials: H
authors.lastname: Rincon-Arano
authors.affiliation: From the Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado 80045.
authors.forename: Hillary F
authors.initials: HF
authors.lastname: Allen
authors.affiliation: the Department of Chemistry, University of Victoria, Victoria, British Columbia V8W 3V6, Canada.
authors.forename: Janessa
authors.initials: J
authors.lastname: Li
authors.affiliation: the Department of Biochemistry and Biophysics and the Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Strahl
authors.affiliation: the Department of Chemistry, University of Victoria, Victoria, British Columbia V8W 3V6, Canada, fhof@uvic.ca.
authors.forename: Fraser
authors.initials: F
authors.lastname: Hof
authors.affiliation: From the Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado 80045, tatiana.kutateladze@ucdenver.edu.
authors.forename: Tatiana G
authors.initials: TG
authors.lastname: Kutateladze
mesh_terms: D047250:Calixarenes / Q000138:chemical synthesis* / Q000737:chemistry*; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D010940:Plant Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D010940:Plant Proteins; D047250:Calixarenes
keywords: PHD finger; calixarene; chromatin; histone; histone methylation; inhibitor