2uxx: Difference between revisions

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.

2UXX is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with CL, FA9 and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2UXX OCA].  

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