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PDBsum entry 5h6r
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Oxidoreductase/transcription/inhibitor
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PDB id
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5h6r
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Contents |
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662 a.a.
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132 a.a.
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14 a.a.
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References listed in PDB file
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Key reference
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Title
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Development and crystallographic evaluation of histone h3 peptide with n-Terminal serine substitution as a potent inhibitor of lysine-Specific demethylase 1.
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Authors
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Y.Amano,
M.Kikuchi,
S.Sato,
S.Yokoyama,
T.Umehara,
N.Umezawa,
T.Higuchi.
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Ref.
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Bioorg Med Chem Lett, 2017,
25,
2617-2624.
[DOI no: ]
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PubMed id
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Abstract
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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.
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