5VAR

Crystal structure of KDM4A tandem TUDOR domain in complex with a tri-methyl lysine competitive inhibitor

5VAR の概要

• エントリーDOI: 10.2210/pdb5var/pdb
• 分子名称: Lysine-specific demethylase 4A, (1R,2S,3R,4S)-3-[(dimethylamino)methyl]-1-phenylbicyclo[2.2.1]heptan-2-ol (3 entities in total)
• 機能のキーワード: kdm4a tandem tudor domain, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 13788.26

構造登録者

Judge, R.A.,Upadhyay, A.K. (登録日: 2017-03-27, 公開日: 2018-03-28, 最終更新日: 2023-10-04)

主引用文献

Upadhyay, A.K.,Judge, R.A.,Li, L.,Pithawalla, R.,Simanis, J.,Bodelle, P.M.,Marin, V.L.,Henry, R.F.,Petros, A.M.,Sun, C.
Targeting lysine specific demethylase 4A (KDM4A) tandem TUDOR domain - A fragment based approach.
Bioorg. Med. Chem. Lett., 28:1708-1713, 2018

PubMed Abstract: The tandem TUDOR domains present in the non-catalytic C-terminal half of the KDM4A, 4B and 4C enzymes play important roles in regulating their chromatin localizations and substrate specificities. They achieve this regulatory role by binding to different tri-methylated lysine residues on histone H3 (H3-K4me3, H3-K23me3) and histone H4 (H4-K20me3) depending upon the specific chromatin environment. In this work, we have used a 2D-NMR based fragment screening approach to identify a novel fragment (1a), which binds to the KDM4A-TUDOR domain and shows modest competition with H3-K4me3 binding in biochemical as well as in vitro cell based assays. A co-crystal structure of KDM4A TUDOR domain in complex with 1a shows that the fragment binds stereo-specifically to the methyl lysine binding pocket forming a network of strong hydrogen bonds and hydrophobic interactions. We anticipate that the fragment 1a can be further developed into a novel allosteric inhibitor of the KDM4 family of enzymes through targeting their C-terminal tandem TUDOR domain.

PubMed: 29691138
DOI: 10.1016/j.bmcl.2018.04.050

実験手法

X-RAY DIFFRACTION (1.83 Å)