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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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PDB id:
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| Name: |
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Transferase/transferase inhibitor
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Title:
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Structural analysis of a phosphoribosylated inhibitor in complex with human nicotinamide phosphoribosyltransferase
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Structure:
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Nicotinamide phosphoribosyltransferase. Chain: a, b. Synonym: namprtase, nampt, pre-b-cell colony-enhancing factor 1, pre- b cell-enhancing factor, visfatin. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: nampt, pbef, pbef1. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.12Å
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R-factor:
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0.189
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R-free:
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0.227
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Authors:
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A.Oh,Y.Ho,M.Zak,Y.Liu,P.Yuen,X.Zheng,S.P.Dragovich,W.Wang
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Key ref:
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A.Oh
et al.
(2014).
Structural and biochemical analyses of the catalysis and potency impact of inhibitor phosphoribosylation by human nicotinamide phosphoribosyltransferase.
Chembiochem,
15,
1121-1130.
PubMed id:
DOI:
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Date:
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08-Jun-13
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Release date:
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11-Jun-14
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PROCHECK
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Headers
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References
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P43490
(NAMPT_HUMAN) -
Nicotinamide phosphoribosyltransferase from Homo sapiens
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Seq:
Struc:
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491 a.a.
472 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.2.4.2.12
- nicotinamide phosphoribosyltransferase.
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Reaction:
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beta-nicotinamide D-ribonucleotide + diphosphate = 5-phospho-alpha-D- ribose 1-diphosphate + nicotinamide + H+
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beta-nicotinamide D-ribonucleotide
Bound ligand (Het Group name = )
matches with 41.30% similarity
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+
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diphosphate
Bound ligand (Het Group name = )
matches with 55.56% similarity
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=
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5-phospho-alpha-D- ribose 1-diphosphate
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+
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nicotinamide
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+
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H(+)
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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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Chembiochem
15:1121-1130
(2014)
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PubMed id:
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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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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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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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