Your browser doesn't support javascript.
loading
Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds.
Horton, John R; Liu, Xu; Gale, Molly; Wu, Lizhen; Shanks, John R; Zhang, Xing; Webber, Philip J; Bell, Joshua S K; Kales, Stephen C; Mott, Bryan T; Rai, Ganesha; Jansen, Daniel J; Henderson, Mark J; Urban, Daniel J; Hall, Matthew D; Simeonov, Anton; Maloney, David J; Johns, Margaret A; Fu, Haian; Jadhav, Ajit; Vertino, Paula M; Yan, Qin; Cheng, Xiaodong.
Affiliation
  • Horton JR; Department of Biochemistry, Emory University, Atlanta, GA 30322, USA.
  • Liu X; Department of Biochemistry, Emory University, Atlanta, GA 30322, USA.
  • Gale M; Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
  • Wu L; Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
  • Shanks JR; Department of Biochemistry, Emory University, Atlanta, GA 30322, USA.
  • Zhang X; Department of Biochemistry, Emory University, Atlanta, GA 30322, USA.
  • Webber PJ; Department of Pharmacology, Emory University, Atlanta, GA 30322, USA; Emory Chemical Biology Discovery Center, Emory University, Atlanta, GA 30322, USA.
  • Bell JSK; Department of Radiation Oncology, Emory University, Atlanta, GA 30322, USA.
  • Kales SC; National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
  • Mott BT; National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
  • Rai G; National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
  • Jansen DJ; National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
  • Henderson MJ; National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
  • Urban DJ; National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
  • Hall MD; National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
  • Simeonov A; National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
  • Maloney DJ; National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
  • Johns MA; Department of Pharmacology, Emory University, Atlanta, GA 30322, USA; Emory Chemical Biology Discovery Center, Emory University, Atlanta, GA 30322, USA.
  • Fu H; 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, G
  • Jadhav A; National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
  • Vertino PM; Department of Radiation Oncology, Emory University, Atlanta, GA 30322, USA; The Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
  • Yan Q; Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address: qin.yan@yale.edu.
  • Cheng X; Department of Biochemistry, Emory University, Atlanta, GA 30322, USA; The Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA. Electronic address: xcheng@emory.edu.
Cell Chem Biol ; 23(7): 769-781, 2016 07 21.
Article in En | MEDLINE | ID: mdl-27427228
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.
Subject(s)
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Database: MEDLINE Main subject: Organometallic Compounds / Enzyme Inhibitors / Retinoblastoma-Binding Protein 2 Limits: Humans Language: En Year: 2016 Type: Article
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Database: MEDLINE Main subject: Organometallic Compounds / Enzyme Inhibitors / Retinoblastoma-Binding Protein 2 Limits: Humans Language: En Year: 2016 Type: Article