2. Academic Validation
  3. Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds

Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds

  • Cell Chem Biol. 2016 Jul 21;23(7):769-781. doi: 10.1016/j.chembiol.2016.06.006.
John R Horton 1,  Xu Liu 1,  Molly Gale 2,  Lizhen Wu 2,  John R Shanks 1,  Xing Zhang 1,  Philip J Webber 3,  Joshua S K Bell 4,  Stephen C Kales 5,  Bryan T Mott 5,  Ganesha Rai 5,  Daniel J Jansen 5,  Mark J Henderson 5,  Daniel J Urban 5,  Matthew D Hall 5,  Anton Simeonov 5,  David J Maloney 5,  Margaret A Johns 3,  Haian Fu 6,  Ajit Jadhav 5,  Paula M Vertino 7,  Qin Yan 8,  Xiaodong Cheng 9
Affiliations

Affiliations

  • 1 Department of Biochemistry, Emory University, Atlanta, GA 30322, USA.
  • 2 Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
  • 3 Department of Pharmacology, Emory University, Atlanta, GA 30322, USA; Emory Chemical Biology Discovery Center, Emory University, Atlanta, GA 30322, USA.
  • 4 Department of Radiation Oncology, Emory University, Atlanta, GA 30322, USA.
  • 5 National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
  • 6 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.
  • 7 Department of Radiation Oncology, Emory University, Atlanta, GA 30322, USA; The Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
  • 8 Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address: [email protected].
  • 9 Department of Biochemistry, Emory University, Atlanta, GA 30322, USA; The Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA. Electronic address: [email protected].
PMID: 27427228 DOI: 10.1016/j.chembiol.2016.06.006
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.

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