4UVC

LSD1(KDM1A)-CoREST in complex with 1-Phenyl-Tranylcypromine

4UVC の概要

• エントリーDOI: 10.2210/pdb4uvc/pdb
• 関連するPDBエントリー: 4UV8 4UV9 4UVA 4UVB
• 分子名称: LYSINE-SPECIFIC HISTONE DEMETHYLASE 1A, REST COREPRESSOR 1, [[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2R,3S,4S)-5-[5-[(1S)-1-azanyl-1,3-diphenyl-propyl]-7,8-dimethyl-2,4-bis(oxidanylidene)-4aH-benzo[g]pteridin-10-yl]-2,3,4-tris(oxidanyl)pentyl] hydrogen phosphate (3 entities in total)
• 機能のキーワード: transcription, histone demethylase
• 由来する生物種: HOMO SAPIENS (HUMAN); 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: 148945.05

構造登録者

Vianello, P.,Botrugno, O.,Cappa, A.,Ciossani, G.,Dessanti, P.,Mai, A.,Mattevi, A.,Meroni, G.,Minucci, S.,Thaler, F.,Tortorici, M.,Trifiro, P.,Valente, S.,Villa, M.,Varasi, M.,Mercurio, C. (登録日: 2014-08-05, 公開日: 2014-09-10, 最終更新日: 2024-01-10)

主引用文献

Vianello, P.,Botrugno, O.A.,Cappa, A.,Ciossani, G.,Dessanti, P.,Mai, A.,Mattevi, A.,Meroni, G.,Minucci, S.,Thaler, F.,Tortorici, M.,Trifiro, P.,Valente, S.,Villa, M.,Varasi, M.,Mercurio, C.
Synthesis, Biological Activity and Mechanistic Insights of 1-Substituted Cyclopropylamine Derivatives: A Novel Class of Irreversible Inhibitors of Histone Demethylase Kdm1A.
Eur.J.Med.Chem., 86C:352-, 2014

PubMed Abstract: Histone demethylase KDM1A (also known as LSD1) has become an attractive therapeutic target for the treatment of cancer as well as other disorders such as viral infections. We report on the synthesis of compounds derived from the expansion of tranylcypromine as a chemical scaffold for the design of novel demethylase inhibitors. These compounds, which are substituted on the cyclopropyl core moiety, were evaluated for their ability to inhibit KDM1A in vitro as well as to function in cells by modulating the expression of Gfi-1b, a well recognized KDM1A target gene. The molecules were all found to covalently inhibit KDM1A and to become increasingly selective against human monoamine oxidases MAO A and MAO B through the introduction of bulkier substituents on the cyclopropylamine ring. Structural and biochemical analysis of selected trans isomers showed that the two stereoisomers are endowed with similar inhibitory activities against KDM1A, but form different covalent adducts with the FAD co-enzyme.

PubMed: 25173853
DOI: 10.1016/J.EJMECH.2014.08.068

実験手法

X-RAY DIFFRACTION (3.1 Å)