title: Selective Inhibition of CBX6: A Methyllysine Reader Protein in the Polycomb Family.
abstract: The polycomb paralogs CBX2, CBX4, CBX6, CBX7, and CBX8 are epigenetic readers that rely on "aromatic cage" motifs to engage their partners' methyllysine side chains. Each CBX carries out distinct functions, yet each includes a highly similar methyllysine-reading chromodomain as a key element. CBX7 is the only chromodomain that has yet been targeted by chemical inhibition. We report a small set of peptidomimetic agents in which a simple chemical modification switches the ligands from one with promiscuity across all polycomb paralogs to one that provides selective inhibition of CBX6. The structural basis for this selectivity, which involves occupancy of a small hydrophobic pocket adjacent to the aromatic cage, was confirmed through molecular dynamics simulations. Our results demonstrate the increases in affinity and selectivity generated by ligands that engage extended regions of chromodomain binding surfaces.
authors.affiliation: Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada.
authors.forename: Natalia
authors.initials: N
authors.lastname: Milosevich
authors.affiliation: Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Gignac
authors.affiliation: Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada.
authors.forename: James
authors.initials: J
authors.lastname: McFarlane
authors.affiliation: Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada.
authors.forename: Chakravarthi
authors.initials: C
authors.lastname: Simhadri
authors.affiliation: Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada.
authors.forename: Shanti
authors.initials: S
authors.lastname: Horvath
authors.affiliation: Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Daze
authors.affiliation: Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada.
authors.forename: Caitlin S
authors.initials: CS
authors.lastname: Croft
authors.affiliation: Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada.
authors.forename: Aman
authors.initials: A
authors.lastname: Dheri
authors.affiliation: Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada.
authors.forename: Taylor T H
authors.initials: TT
authors.lastname: Quon
authors.affiliation: Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada.
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Douglas
authors.affiliation: Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada.
authors.forename: Jeremy E
authors.initials: JE
authors.lastname: Wulff
authors.affiliation: Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada.
authors.forename: Irina
authors.initials: I
authors.lastname: Paci
authors.affiliation: Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada.
authors.forename: Fraser
authors.initials: F
authors.lastname: Hof
keywords: CBX6; Epigenetics; Polycomb Group proteins; methyllysine reader proteins; peptidomimetics