Background

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.

Protein Classification

Oxidoreductase/repressor

Structure Weight

101692.78 Da

Polymer

1

Molecule

Lysine-specific Histone Demethylase 1

Chain Length

666 amino acids

Polymer

2

Molecule

Rest Corepressor 1

Chain Length

235 amino acids

PDB ID

2UXX

MMDB ID

59741

Source

E.coli

Method

X-Ray Diffraction

Resolution

2.74 Å

Ligand Chemical Component

chloride ion, FA9, glycerol

Gene Name

RCOR1

Synonyms

COREST, KIAA0071, RCOR, protein CoREST, REST corepressor, REST corepressor

UniProt ID

Q9UKL0

Gene ID

23186

Chromosome Location

14q32.31-q32.32

Function

DNA binding; protein binding

Gene Name

KDM1

Synonyms

RP1-184J9.1; AOF2; BHC110; KIAA0601; LSD1;BRAF35-HDAC complex protein BHC110; FAD-binding protein BRAF35-HDAC complex, 110 kDa subunit; amine oxidase (flavin containing) domain 2; lysine-specific histone demethylase 1; Flavin-containing amine oxidase domain-containing protein 2; lysine (K)-specific demethylase 1; EC 1.-.-.-; fad binding protein braf35 hdac complex 110 kda s; amine oxidase (flavin containing) domain 2

UniProt ID

O60341

Gene ID

23028

Chromosome Location

1p36.12

Function

FAD binding; electron carrier activity; oxidoreductase activity; transcription factor activity; transcription factor binding

Reference

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, 2007,46: 8058-8065