5X60

Crystal structure of LSD1-CoREST in complex with peptide 9

Summary for 5X60

• Entry DOI: 10.2210/pdb5x60/pdb
• Descriptor: Lysine-specific histone demethylase 1A, REST corepressor 1, PEPTIDE SRTMQTARKSTGGKAPRKQL, ... (6 entities in total)
• Functional Keywords: demethylase, amine oxidase, chromatin, histone, fad, corepressor, oxidoreductase-transcription complex, oxidoreductase/transcription
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : O60341 Q9UKL0
• Total number of polymer chains: 3
• Total formula weight: 93454.39

Authors

Kikuchi, M.,Amano, Y.,Sato, S.,Yokoyama, S.,Umezawa, N.,Higuchi, T.,Umehara, T. (deposition date: 2017-02-20, release date: 2017-04-12, Last modification date: 2023-11-22)

Primary citation

Amano, Y.,Kikuchi, M.,Sato, S.,Yokoyama, S.,Umehara, T.,Umezawa, N.,Higuchi, T.
Development and crystallographic evaluation of histone H3 peptide with N-terminal serine substitution as a potent inhibitor of lysine-specific demethylase 1.
Bioorg. Med. Chem., 25:2617-2624, 2017

PubMed Abstract: Lysine-specific demethylase 1 (LSD1/KDM1A) is a flavoenzyme demethylase, which removes mono- and dimethyl groups from histone H3 Lys4 (H3K4) or Lys9 (H3K9) in complexes with several nuclear proteins. Since LSD1 is implicated in the tumorigenesis and progression of various cancers, LSD1-specific inhibitors are considered as potential anti-cancer agents. A modified H3 peptide with substitution of Lys4 to Met [H3K4M] is already known to be a potent competitive inhibitor of LSD1. In this study, we synthesized a series of H3K4M peptide derivatives and evaluated their LSD1-inhibitory activities in vitro. We found that substitutions of the N-terminal amino acid with amino acids having a larger side chain were generally not tolerated, but substitution of Ala1 to Ser unexpectedly resulted in more potent inhibitory activity toward LSD1. X-ray crystallographic analysis of H3K4M derivatives bound to the LSD1·CoREST complex revealed the presence of additional hydrogen bonding between the N-terminal Ser residue of the H3 peptide derivative and LSD1. The present structural and biochemical findings will be helpful for obtaining more potent peptidic inhibitors of LSD1.

PubMed: 28336409
DOI: 10.1016/j.bmc.2017.03.016

Experimental method

X-RAY DIFFRACTION (2.69 Å)