4UVC: Lsd1(kdm1a)-corest In Complex With 1-phenyl-tranylcypromine

Citation:
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.
PDB ID: 4UVCDownload
MMDB ID: 123130
PDB Deposition Date: 2014/8/5
Updated in MMDB: 2014/09
Experimental Method:
x-ray diffraction
Resolution: 3.1  Å
Source Organism:
Similar Structures:
Biological Unit for 4UVC: dimeric; determined by author and by software (PISA)
Molecular Components in 4UVC
Label Count Molecule
Proteins (2 molecules)
1
Lysine-specific Histone Demethylase 1A(Gene symbol: KDM1A)
Molecule annotation
1
Rest Corepressor 1(Gene symbol: RCOR1)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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