title: Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds.
abstract: The KDM5/JARID1 family of Fe(II)- and α-ketoglutarate-dependent demethylases removes methyl groups from methylated lysine 4 of histone H3. Accumulating evidence supports a role for KDM5 family members as oncogenic drivers. We compare the in vitro inhibitory properties and binding affinity of ten diverse compounds with all four family members, and present the crystal structures of the KDM5A-linked Jumonji domain in complex with eight of these inhibitors in the presence of Mn(II). All eight inhibitors structurally examined occupy the binding site of α-ketoglutarate, but differ in their specific binding interactions, including the number of ligands involved in metal coordination. We also observed inhibitor-induced conformational changes in KDM5A, particularly those residues involved in the binding of α-ketoglutarate, the anticipated peptide substrate, and intramolecular interactions. We discuss how particular chemical moieties contribute to inhibitor potency and suggest strategies that might be utilized in the successful design of selective and potent epigenetic inhibitors.
authors.affiliation: Department of Biochemistry, Emory University, Atlanta, GA 30322, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Horton
authors.affiliation: Department of Biochemistry, Emory University, Atlanta, GA 30322, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Molly
authors.initials: M
authors.lastname: Gale
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Lizhen
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Emory University, Atlanta, GA 30322, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Shanks
authors.affiliation: Department of Biochemistry, Emory University, Atlanta, GA 30322, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Emory University, Atlanta, GA 30322, USA; Emory Chemical Biology Discovery Center, Emory University, Atlanta, GA 30322, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Webber
authors.affiliation: Department of Radiation Oncology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Joshua S K
authors.initials: JSK
authors.lastname: Bell
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Kales
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Mott
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Ganesha
authors.initials: G
authors.lastname: Rai
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Jansen
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Henderson
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Urban
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hall
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
authors.affiliation: Department of Pharmacology, Emory University, Atlanta, GA 30322, USA; Emory Chemical Biology Discovery Center, Emory University, Atlanta, GA 30322, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Johns
authors.affiliation: Department of Pharmacology, Emory University, Atlanta, GA 30322, USA; Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA; Emory Chemical Biology Discovery Center, Emory University, Atlanta, GA 30322, USA; The Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.affiliation: Department of Radiation Oncology, Emory University, Atlanta, GA 30322, USA; The Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Vertino
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address: qin.yan@yale.edu.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yan
authors.affiliation: Department of Biochemistry, Emory University, Atlanta, GA 30322, USA; The Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA. Electronic address: xcheng@emory.edu.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Cheng
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D056485:Retinoblastoma-Binding Protein 2 / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; C070050:KDM5A protein, human; D056485:Retinoblastoma-Binding Protein 2