5LY2

JMJD2A/ KDM4A COMPLEXED WITH NI(II), NOG AND Macrocyclic PEPTIDE Inhibitor CP2_R6Kme3 (13-mer)

5LY2 の概要

• エントリーDOI: 10.2210/pdb5ly2/pdb
• 関連するPDBエントリー: 2OX0 2YBP 4AI9 4BIS 4V2V 5LY1
• 分子名称: Lysine-specific demethylase 4A, CP2_R6Kme3, NICKEL (II) ION, ... (8 entities in total)
• 機能のキーワード: jmjd2a, kdm4a, oxidoreductase, non-heme, iron, 2-oxoglutarate, dioxygenase, oxygenase, double-stranded beta helix, dsbh, facial triad, demethylase, histone, jmjc domain, metal binding protein, epigenetic and transcription regulation, chromatin regulator, hydroxylation
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 186740.28

構造登録者

Chowdhury, R.,Madden, S.K.,Hopkinson, R.,Schofield, C.J. (登録日: 2016-09-23, 公開日: 2017-04-12, 最終更新日: 2024-01-17)

主引用文献

Kawamura, A.,Munzel, M.,Kojima, T.,Yapp, C.,Bhushan, B.,Goto, Y.,Tumber, A.,Katoh, T.,King, O.N.,Passioura, T.,Walport, L.J.,Hatch, S.B.,Madden, S.,Muller, S.,Brennan, P.E.,Chowdhury, R.,Hopkinson, R.J.,Suga, H.,Schofield, C.J.
Highly selective inhibition of histone demethylases by de novo macrocyclic peptides.
Nat Commun, 8:14773-14773, 2017

PubMed Abstract: The JmjC histone demethylases (KDMs) are linked to tumour cell proliferation and are current cancer targets; however, very few highly selective inhibitors for these are available. Here we report cyclic peptide inhibitors of the KDM4A-C with selectivity over other KDMs/2OG oxygenases, including closely related KDM4D/E isoforms. Crystal structures and biochemical analyses of one of the inhibitors (CP2) with KDM4A reveals that CP2 binds differently to, but competes with, histone substrates in the active site. Substitution of the active site binding arginine of CP2 to N-ɛ-trimethyl-lysine or methylated arginine results in cyclic peptide substrates, indicating that KDM4s may act on non-histone substrates. Targeted modifications to CP2 based on crystallographic and mass spectrometry analyses results in variants with greater proteolytic robustness. Peptide dosing in cells manifests KDM4A target stabilization. Although further development is required to optimize cellular activity, the results reveal the feasibility of highly selective non-metal chelating, substrate-competitive inhibitors of the JmjC KDMs.

PubMed: 28382930
DOI: 10.1038/ncomms14773

実験手法

X-RAY DIFFRACTION (2.43 Å)