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PDBsum entry 5lbq
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Oxidoreductase/repressor
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PDB id
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5lbq
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References listed in PDB file
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Key reference
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Title
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Polymyxins and quinazolines are lsd1/kdm1a inhibitors with unusual structural features.
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Authors
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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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Ref.
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Sci Adv, 2016,
2,
e1601017.
[DOI no: ]
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PubMed id
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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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