Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds

• Type of Material: Article
• Authors: John Horton, Emory University; Xu Liu, Emory University; Molly Gale, Yale School of Medicine; Lizhen Wu, Yale School of Medicine; John R. Shanks, Emory University; Xing Zhang, Emory University; Philip J. Webber, Emory University; Joshua S.K. Bell, Emory University; Stephen C Kales, National Institutes of Health; Bryan T Mott, National Institutes of Health; Ganesha Rai, National Institutes of Health; Daniel J Jansen, National Institutes of Health; Mark J Henderson, National Institutes of Health; Daniel J Urban, National Institutes of Health; Matthew D Hall, National Institutes of Health; Anton Simeonov, National Institutes of Health; David J Maloney, National Institutes of Health; Margaret A. Johns, Emory University; Haian Fu, Emory University; Ajit Jadhav, National Institutes of Health; Paula Vertino, Emory University; Qin Yan, Yale School of Medicine; Xiaodong Cheng, Emory University
• Language: English
• Date: 2016-07-21
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Elsevier Ltd
• Final Published Version (URL): http://dx.doi.org/10.1016/j.chembiol.2016.06.006
• Title of Journal or Parent Work: Cell Chemical Biology
• ISSN: 2451-9456
• Volume: 23
• Issue: 7
• Start Page: 769
• End Page: 781
• Grant/Funding Information: This project has been funded in part with Federal funds from the National Cancer Institute (NCI), National Institutes of Health (NIH), under NCI Chemical Biology Consortium Contract No. HHSN261200800001E (to H.F.), NIH grants (GM114306-02 to X.C. and CA077337 to P.M.V.), American Cancer Society Research Scholar Grant (RSG-13-384-01-DMC to Q.Y.) and DoD Breast Cancer Research Program Award (W81XWH-14-1-0308 to Q.Y.), National Science Foundation Graduate Research Fellowship (DGE-1122492 to M.G.), Leslie H. Warner Postdoctoral Fellowship (to L.W.), NIH predoctoral NRSA F31 fellowship (CA186676 to J.S.K.B.), developmental funds (to X.C. and P.M.V.) from the Winship Cancer Institute of Emory University Cancer Center Support Grant P30-CA138292 and funds from the Arthur and Sarah Merrill Foundation (to X.C.).; The Department of Biochemistry of Emory University School of Medicine supported the use of the Southeast Regional Collaborative Access Team (SERCAT) synchrotron beamlines at the Advanced Photon Source of Argonne National Laboratory.
• Keywords: PROTEINS; BREAST-CANCER; Biochemistry & Molecular Biology; DERIVATIVES; DOMAIN; BINDING; IDENTIFICATION; Science & Technology; FAMILY; JARID1B; Life Sciences & Biomedicine; RBP2; CELL PENETRANT INHIBITORS
• Research Categories: Biology, Molecular; Chemistry, Biochemistry

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.