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PDBsum entry 4l4l
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Transferase/transferase inhibitor
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PDB id
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4l4l
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References listed in PDB file
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Key reference
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Title
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Structural and biochemical analyses of the catalysis and potency impact of inhibitor phosphoribosylation by human nicotinamide phosphoribosyltransferase.
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Authors
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A.Oh,
Y.C.Ho,
M.Zak,
Y.Liu,
X.Chen,
P.W.Yuen,
X.Zheng,
Y.Liu,
P.S.Dragovich,
W.Wang.
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Ref.
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Chembiochem, 2014,
15,
1121-1130.
[DOI no: ]
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PubMed id
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Abstract
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Prolonged inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is a
strategy for targeting cancer metabolism. Many NAMPT inhibitors undergo
NAMPT-catalyzed phosphoribosylation (pRib), a property often correlated with
their cellular potency. To understand this phenomenon and facilitate drug
design, we analyzed a potent cellularly active NAMPT inhibitor (GNE-617). A
crystal structure of pRib-GNE-617 in complex with NAMPT protein revealed a
relaxed binding mode. Consistently, the adduct formation resulted in tight
binding and strong product inhibition. In contrast, a biochemically equipotent
isomer of GNE-617 (GNE-643) also formed pRib adducts but displayed significantly
weaker cytotoxicity. Structural analysis revealed an altered ligand conformation
of GNE-643, thus suggesting weak association of the adducts with NAMPT. Our data
support a model for cellularly active NAMPT inhibitors that undergo
NAMPT-catalyzed phosphoribosylation to produce pRib adducts that retain
efficient binding to the enzyme.
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