5A3N

Crystal structure of human PLU-1 (JARID1B) in complex with KDOAM25a

5A3N の概要

• エントリーDOI: 10.2210/pdb5a3n/pdb
• 分子名称: LYSINE-SPECIFIC DEMETHYLASE 5B, ZINC ION, MANGANESE (II) ION, ... (9 entities in total)
• 機能のキーワード: oxidoreductase
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Nucleus : Q9UGL1
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 56844.42

構造登録者

Srikannathasan, V.,Johansson, C.,Gileadi, C.,Nuzzi, A.,Ruda, G.F.,Kopec, J.,von Delft, F.,Arrowsmith, C.H.,Bountra, C.,Edwards, A.,Brennan, P.,Oppermann, U. (登録日: 2015-06-02, 公開日: 2015-07-08, 最終更新日: 2024-05-08)

主引用文献

Tumber, A.,Nuzzi, A.,Hookway, E.S.,Hatch, S.B.,Velupillai, S.,Johansson, C.,Kawamura, A.,Savitsky, P.,Yapp, C.,Szykowska, A.,Wu, N.,Bountra, C.,Strain-Damerell, C.,Burgess-Brown, N.A.,Ruda, G.F.,Fedorov, O.,Munro, S.,England, K.S.,Nowak, R.P.,Schofield, C.J.,La Thangue, N.B.,Pawlyn, C.,Davies, F.,Morgan, G.,Athanasou, N.,Muller, S.,Oppermann, U.,Brennan, P.E.
Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells.
Cell Chem Biol, 24:371-380, 2017

PubMed Abstract: Methylation of lysine residues on histone tail is a dynamic epigenetic modification that plays a key role in chromatin structure and gene regulation. Members of the KDM5 (also known as JARID1) sub-family are 2-oxoglutarate (2-OG) and Fe-dependent oxygenases acting as histone 3 lysine 4 trimethyl (H3K4me3) demethylases, regulating proliferation, stem cell self-renewal, and differentiation. Here we present the characterization of KDOAM-25, an inhibitor of KDM5 enzymes. KDOAM-25 shows biochemical half maximal inhibitory concentration values of <100 nM for KDM5A-D in vitro, high selectivity toward other 2-OG oxygenases sub-families, and no off-target activity on a panel of 55 receptors and enzymes. In human cell assay systems, KDOAM-25 has a half maximal effective concentration of ∼50 μM and good selectivity toward other demethylases. KDM5B is overexpressed in multiple myeloma and negatively correlated with the overall survival. Multiple myeloma MM1S cells treated with KDOAM-25 show increased global H3K4 methylation at transcriptional start sites and impaired proliferation.

PubMed: 28262558
DOI: 10.1016/j.chembiol.2017.02.006

実験手法

X-RAY DIFFRACTION (2 Å)