5IVC

Linked KDM5A Jmj Domain Bound to the Inhibitor N3 (4'-[(2-phenylethyl)carbamoyl][2,2'-bipyridine]-4-carboxylic acid)

5IVC の概要

• エントリーDOI: 10.2210/pdb5ivc/pdb
• 関連するPDBエントリー: 5ISL 5IVB 5IVE 5IVF 5IVJ 5IVV 5IVY 5IW0 5IWF
• 分子名称: Lysine-specific demethylase 5A, 4'-[(2-phenylethyl)carbamoyl][2,2'-bipyridine]-4-carboxylic acid, MANGANESE (II) ION, ... (6 entities in total)
• 機能のキーワード: demethylase inhibition, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus, nucleolus : P29375
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38625.44

構造登録者

Horton, J.R.,Cheng, X. (登録日: 2016-03-20, 公開日: 2016-07-27, 最終更新日: 2023-09-27)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.573 Å)