6G5X

Crystal Structure of KDM4A with compound YP-02-145

6G5X の概要

• エントリーDOI: 10.2210/pdb6g5x/pdb
• 分子名称: Lysine-specific demethylase 4A, ZINC ION, NICKEL (II) ION, ... (8 entities in total)
• 機能のキーワード: kdm4a, ligand binding, drug design, inhibitor design, cancer, epigenetics, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 85151.74

構造登録者

Malecki, P.H.,Carter, D.M.,Gohlke, U.,Specker, E.,Nazare, M.,Weiss, M.S.,Heinemann, U. (登録日: 2018-03-30, 公開日: 2019-04-10, 最終更新日: 2024-01-31)

主引用文献

Carter, D.M.,Specker, E.,Malecki, P.H.,Przygodda, J.,Dudaniec, K.,Weiss, M.S.,Heinemann, U.,Nazare, M.,Gohlke, U.
Enhanced Properties of a Benzimidazole Benzylpyrazole Lysine Demethylase Inhibitor: Mechanism-of-Action, Binding Site Analysis, and Activity in Cellular Models of Prostate Cancer.
J.Med.Chem., 64:14266-14282, 2021

PubMed Abstract: Jumonji domain-containing lysine demethylase (KDM) enzymes are encoded by genes of the KDM superfamily. Activities of the KDM4 subfamily promote aggressive phenotypes associated with prostate cancer (PCa). Previously, we discovered a benzimidazole pyrazole molecule that inhibited KDM4 isoforms with properties tractable for development. Here, we demonstrate that a benzyl-substituted variant of this inhibitor exhibits improved potency in biochemical assays, is cell-permeable, and kills PCa cells at low micromolar concentrations. By X-ray crystallography and kinetics-based assays, we demonstrate that the mechanism of inhibition is complex, proceeding via competition with the enzyme for binding of active-site Fe and by populating a distal site on the enzyme surface. Furthermore, we provide evidence that the inhibitor's cytostatic properties arise from direct intracellular inhibition of KDM4 enzymes. PCa cells treated with the inhibitor exhibit reduced expression of genes regulated by the androgen receptor, an outcome accompanied by epigenetic maintenance of a heterochromatic state.

PubMed: 34555281
DOI: 10.1021/acs.jmedchem.1c00693

実験手法

X-RAY DIFFRACTION (1.78 Å)