2UXX

Human LSD1 Histone Demethylase-CoREST in complex with an FAD- tranylcypromine adduct

Summary for 2UXX

• Entry DOI: 10.2210/pdb2uxx/pdb
• Related: 2COM 2H94 2IW5 2UXN
• Descriptor: LYSINE-SPECIFIC HISTONE DEMETHYLASE 1, REST COREPRESSOR 1, FAD-trans-2-Phenylcyclopropylamine Adduct, ... (6 entities in total)
• Functional Keywords: oxidoreductase-repressor complex, histone demethylase, oxidoreductase, nuclear protein, phosphorylation, transcription regulation, tranylcypromine, chromatin regulator, nucleosomes, transcription, host-virus interaction, chromatin demethylation, fad, lsd1, corest, repressor, depression, oxidoreductase/repressor
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 2
• Total formula weight: 101691.88

Authors

Yang, M.,Culhane, J.C.,Machius, M.,Cole, P.A.,Yu, H. (deposition date: 2007-03-30, release date: 2007-08-21, Last modification date: 2024-05-08)

Primary citation

Yang, M.,Culhane, J.C.,Szewczuk, L.M.,Jalili, P.,Ball, H.L.,Machius, M.,Cole, P.A.,Yu, H.
Structural Basis for the Inhibition of the Lsd1 Histone Demethylase by the Antidepressant Trans-2-Phenylcyclopropylamine.
Biochemistry, 46:8058-, 2007

PubMed Abstract: Histone modifications, such as acetylation and methylation, are important epigenetic marks that regulate diverse biological processes that use chromatin as the template, including transcription. Dysregulation of histone acetylation and methylation leads to the silencing of tumor suppressor genes and contributes to cancer progression. Inhibitors of enzymes that catalyze the addition and removal of these epigenetic marks thus have therapeutic potential for treating cancer. Lysine-specific demethylase 1 (LSD1) is the first discovered histone lysine demethylase and, with the help of its cofactor CoREST, specifically demethylates mono- and dimethylated histone H3 lysine 4 (H3-K4), thus repressing transcription. Because LSD1 belongs to the family of flavin adenine dinucleotide (FAD)-dependent amine oxidases, certain inhibitors of monoamine oxidases (MAOs), including the clinically used antidepressant trans-2-phenylcyclopropylamine (PCPA; tranylcypromine; Parnate), are also capable of inhibiting LSD1. In this study, we have further measured the kinetic parameters of the inhibition of LSD1 by PCPA and determined the crystal structure of LSD1-CoREST in the presence of PCPA. Our structural and mass spectrometry analyses are consistent with PCPA forming a covalent adduct with FAD in LSD1 that is distinct from the FAD-PCPA adduct of MAO B. The structure also reveals that the phenyl ring of the FAD-PCPA adduct in LSD1 does not form extensive interactions with active-site residues. This study thus provides the basis for designing more potent inhibitors of LSD1 that contain substitutions on the phenyl ring of PCPA to fully engage neighboring residues.

PubMed: 17569509
DOI: 10.1021/BI700664Y

Experimental method

X-RAY DIFFRACTION (2.74 Å)