2XAF

Crystal structure of LSD1-CoREST in complex with para-bromo-(+)-cis-2- phenylcyclopropyl-1-amine

2XAF の概要

• エントリーDOI: 10.2210/pdb2xaf/pdb
• 関連するPDBエントリー: 2COM 2H94 2IW5 2UXN 2UXX 2V1D 2X0L 2XAG 2XAH 2XAJ 2XAQ 2XAS
• 分子名称: LYSINE-SPECIFIC HISTONE DEMETHYLASE 1, REST COREPRESSOR 1, FLAVIN-ADENINE DINUCLEOTIDE, ... (4 entities in total)
• 機能のキーワード: amine oxidase, chromatin regulator, histone inhibitor binding, methylation, nucleosome core, oxidoreductase, oxidoreductase-repressor complex, chromatin remodelling, transcription
• 由来する生物種: HOMO SAPIENS; 詳細
• 細胞内の位置: Nucleus: O60341 Q9UKL0
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 147127.05

構造登録者

Binda, C.,Valente, S.,Romanenghi, M.,Pilotto, S.,Cirilli, R.,Karytinos, A.,Ciossani, G.,Botrugno, O.A.,Forneris, F.,Tardugno, M.,Edmondson, D.E.,Minucci, S.,Mattevi, A.,Mai, A. (登録日: 2010-03-31, 公開日: 2010-05-05, 最終更新日: 2024-05-08)

主引用文献

Binda, C.,Valente, S.,Romanenghi, M.,Pilotto, S.,Cirilli, R.,Karytinos, A.,Ciossani, G.,Botrugno, O.A.,Forneris, F.,Tardugno, M.,Edmondson, D.E.,Minucci, S.,Mattevi, A.,Mai, A.
Biochemical, Structural, and Biological Evaluation of Tranylcypromine Derivatives as Inhibitors of Histone Demethylases Lsd1 and Lsd2.
J.Am.Chem.Soc., 132:6827-, 2010

PubMed Abstract: LSD1 and LSD2 histone demethylases are implicated in a number of physiological and pathological processes, ranging from tumorigenesis to herpes virus infection. A comprehensive structural, biochemical, and cellular study is presented here to probe the potential of these enzymes for epigenetic therapies. This approach employs tranylcypromine as a chemical scaffold for the design of novel demethylase inhibitors. This drug is a clinically validated antidepressant known to target monoamine oxidases A and B. These two flavoenzymes are structurally related to LSD1 and LSD2. Mechanistic and crystallographic studies of tranylcypromine inhibition reveal a lack of selectivity and differing covalent modifications of the FAD cofactor depending on the enantiomeric form. These findings are pharmacologically relevant, since tranylcypromine is currently administered as a racemic mixture. A large set of tranylcypromine analogues were synthesized and screened for inhibitory activities. We found that the common evolutionary origin of LSD and MAO enzymes, despite their unrelated functions and substrate specificities, is reflected in related ligand-binding properties. A few compounds with partial enzyme selectivity were identified. The biological activity of one of these new inhibitors was evaluated with a cellular model of acute promyelocytic leukemia chosen since its pathogenesis includes aberrant activities of several chromatin modifiers. Marked effects on cell differentiation and an unprecedented synergistic activity with antileukemia drugs were observed. These data demonstrate that these LSD1/2 inhibitors are of potential relevance for the treatment of promyelocytic leukemia and, more generally, as tools to alter chromatin state with promise of a block of tumor progression.

PubMed: 20415477
DOI: 10.1021/JA101557K

実験手法

X-RAY DIFFRACTION (3.25 Å)