5IVF

Linked KDM5A Jmj Domain Bound to the Inhibitor N10 8-(1-methyl-1H-imidazol-4-yl)-2-(4,4,4-trifluorobutoxy)pyrido[3,4-d]pyrimidin-4-ol

Summary for 5IVF

• Entry DOI: 10.2210/pdb5ivf/pdb
• Related: 5ISL 5IVB 5IVC 5IVE 5IVJ 5IVV 5IVY 5IW0 5IWF
• Descriptor: Lysine-specific demethylase 5A, 8-(1-methyl-1H-imidazol-4-yl)-2-(4,4,4-trifluorobutoxy)pyrido[3,4-d]pyrimidin-4-ol, MANGANESE (II) ION, ... (4 entities in total)
• Functional Keywords: demethylase inhibition, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus, nucleolus : P29375
• Total number of polymer chains: 1
• Total formula weight: 38353.07

Authors

Horton, J.R.,Cheng, X. (deposition date: 2016-03-20, release date: 2016-07-27, Last modification date: 2023-09-27)

Primary citation

Horton, J.R.,Liu, X.,Gale, M.,Wu, L.,Shanks, J.R.,Zhang, X.,Webber, P.J.,Bell, J.S.,Kales, S.C.,Mott, B.T.,Rai, G.,Jansen, D.J.,Henderson, M.J.,Urban, D.J.,Hall, M.D.,Simeonov, A.,Maloney, D.J.,Johns, M.A.,Fu, H.,Jadhav, A.,Vertino, P.M.,Yan, Q.,Cheng, X.
Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds.
Cell Chem Biol, 23:769-781, 2016

PubMed 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.

PubMed: 27427228
DOI: 10.1016/j.chembiol.2016.06.006

Experimental method

X-RAY DIFFRACTION (1.683 Å)