4L4L

Structural Analysis of a Phosphoribosylated Inhibitor in Complex with Human Nicotinamide Phosphoribosyltransferase

Summary for 4L4L

• Entry DOI: 10.2210/pdb4l4l/pdb
• Related: 4L4M
• Descriptor: Nicotinamide phosphoribosyltransferase, 6-({4-[(3,5-difluorophenyl)sulfonyl]benzyl}carbamoyl)-1-(5-O-phosphono-beta-D-ribofuranosyl)imidazo[1,2-a]pyridin-1-ium, PHOSPHATE ION, ... (5 entities in total)
• Functional Keywords: transferase, inhibitor prpp adduct, active site, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P43490
• Total number of polymer chains: 2
• Total formula weight: 115731.89

Authors

Oh, A.,Ho, Y.,Zak, M.,Liu, Y.,Yuen, P.,Zheng, X.,Dragovich, S.P.,Wang, W. (deposition date: 2013-06-08, release date: 2014-06-11, Last modification date: 2024-02-28)

Primary citation

Oh, A.,Ho, Y.C.,Zak, M.,Liu, Y.,Chen, X.,Yuen, P.W.,Zheng, X.,Liu, Y.,Dragovich, P.S.,Wang, W.
Structural and biochemical analyses of the catalysis and potency impact of inhibitor phosphoribosylation by human nicotinamide phosphoribosyltransferase.
Chembiochem, 15:1121-1130, 2014

PubMed Abstract: 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.

PubMed: 24797455
DOI: 10.1002/cbic.201402023

Experimental method

X-RAY DIFFRACTION (2.122 Å)