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PDBsum entry 5l3g
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Oxidoreductase/repressor
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PDB id
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5l3g
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Contents |
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666 a.a.
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133 a.a.
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11 a.a.
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PDB id:
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| Name: |
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Oxidoreductase/repressor
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Title:
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Lsd1-corest1 in complex with polymyxin e (colistin)
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Structure:
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Lysine-specific histone demethylase 1a. Chain: a. Synonym: braf35-hdac complex protein bhc110,flavin-containing amine oxidase domain-containing protein 2. Engineered: yes. Rest corepressor 1. Chain: b. Synonym: protein corest. Engineered: yes.
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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 bl21(de3). Expression_system_taxid: 469008. Expression_system_variant: rp plus. Gene: rcor1, kiaa0071, rcor. Expression_system_variant: rosetta.
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Resolution:
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3.10Å
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R-factor:
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0.173
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R-free:
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0.197
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Authors:
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V.Speranzini,D.Rotili,G.Ciossani,S.Pilotto,M.Forgione,A.Lucidi, F.Forneris,S.Velankar,A.Mai,A.Mattevi
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Key ref:
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V.Speranzini
et al.
(2016).
Polymyxins and quinazolines are LSD1/KDM1A inhibitors with unusual structural features.
Sci Adv,
2,
e1601017.
PubMed id:
DOI:
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Date:
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10-Apr-16
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Release date:
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21-Sep-16
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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.
666 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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Sci Adv
2:e1601017
(2016)
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PubMed id:
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Polymyxins and quinazolines are LSD1/KDM1A inhibitors with unusual structural features.
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V.Speranzini,
D.Rotili,
G.Ciossani,
S.Pilotto,
B.Marrocco,
M.Forgione,
A.Lucidi,
F.Forneris,
P.Mehdipour,
S.Velankar,
A.Mai,
A.Mattevi.
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ABSTRACT
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Because of its involvement in the progression of several malignant tumors, the
histone lysine-specific demethylase 1 (LSD1) has become a prominent drug target
in modern medicinal chemistry research. We report on the discovery of two
classes of noncovalent inhibitors displaying unique structural features. The
antibiotics polymyxins bind at the entrance of the substrate cleft, where their
highly charged cyclic moiety interacts with a cluster of positively charged
amino acids. The same site is occupied by quinazoline-based compounds, which
were found to inhibit the enzyme through a most peculiar mode because they form
a pile of five to seven molecules that obstruct access to the active center.
These data significantly indicate unpredictable strategies for the development
of epigenetic inhibitors.
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