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Structural and Biochemical Analyses of the Catalysis and Potency Impact of Inhibitor Phosphoribosylation by Human Nicotinamide PhosphoribosyltransferaseStructural and Biochemical Analyses of the Catalysis and Potency Impact of Inhibitor Phosphoribosylation by Human Nicotinamide Phosphoribosyltransferase
Structural highlights
Publication Abstract from PubMedProlonged 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. Structural and biochemical analyses of the catalysis and potency impact of inhibitor phosphoribosylation by human nicotinamide phosphoribosyltransferase.,Oh A, Ho YC, Zak M, Liu Y, Chen X, Yuen PW, Zheng X, Liu Y, Dragovich PS, Wang W Chembiochem. 2014 May 26;15(8):1121-30. doi: 10.1002/cbic.201402023. Epub 2014, May 5. PMID:24797455[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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