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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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PDB id:
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| Name: |
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Oxidoreductase/transcription/inhibitor
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Title:
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Crystal structure of lsd1-corest in complex with peptide 13
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Structure:
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Lysine-specific histone demethylase 1a. Chain: a. Fragment: unp residues 172-833. Synonym: braf35-hdac complex protein bhc110,flavin-containing amine oxidase domain-containing protein 2. Engineered: yes. Rest corepressor 1. Chain: b. Fragment: unp residues 308-440.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: kdm1a, aof2, kdm1, kiaa0601, lsd1. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: rcor1, kiaa0071, rcor. Synthetic: yes. Organism_taxid: 9606
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Resolution:
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2.60Å
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R-factor:
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0.217
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R-free:
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0.231
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Authors:
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M.Kkuchi,Y.Amano,S.Sato,S.Yokoyama,N.Umezawa,T.Higuchi,T.Umehara
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Key ref:
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Y.Amano
et al.
(2017).
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 Lett,
25,
2617-2624.
PubMed id:
DOI:
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Date:
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14-Nov-16
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Release date:
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12-Apr-17
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PROCHECK
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Headers
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References
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O60341
(KDM1A_HUMAN) -
Lysine-specific histone demethylase 1A from Homo sapiens
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Seq:
Struc:
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852 a.a.
662 a.a.
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Enzyme class:
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Chain A:
E.C.1.14.99.66
- [histone-H3]-N(6),N(6)-dimethyl-L-lysine(4) FAD-dependent demethylase.
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Reaction:
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N6,N6-dimethyl-L-lysyl4-[histone H3] + 2 A + 2 H2O = L-lysyl4- [histone H3] + 2 formaldehyde + 2 AH2
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N(6),N(6)-dimethyl-L-lysyl(4)-[histone H3]
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+
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2
×
A
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+
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2
×
H2O
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=
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L-lysyl(4)- [histone H3]
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+
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2
×
formaldehyde
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+
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2
×
AH2
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Bioorg Med Chem Lett
25:2617-2624
(2017)
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PubMed id:
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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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Y.Amano,
M.Kikuchi,
S.Sato,
S.Yokoyama,
T.Umehara,
N.Umezawa,
T.Higuchi.
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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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Links
