4L4M

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

4L4M の概要

• エントリーDOI: 10.2210/pdb4l4m/pdb
• 関連するPDBエントリー: 4L4L
• 分子名称: Nicotinamide phosphoribosyltransferase, N-{4-[(3,5-difluorophenyl)sulfonyl]benzyl}imidazo[1,2-a]pyridine-7-carboxamide, PHOSPHATE ION, ... (5 entities in total)
• 機能のキーワード: transferase, inhibitor, active site, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus: P43490
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 115243.62

構造登録者

Oh, A.,Ho, Y.,Zak, M.,Liu, Y.,Yuen, P.,Zheng, X.,Dragovich, S.P.,Wang, W. (登録日: 2013-06-08, 公開日: 2014-06-11, 最終更新日: 2024-02-28)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.445 Å)