4O1C

The crystal structures of a mutant NAMPT H191R

4O1C の概要

• エントリーDOI: 10.2210/pdb4o1c/pdb
• 関連するPDBエントリー: 4O13 4O14 4O15 4O16 4O17 4O18 4O19 4O1A 4O1B 4O1D 4O28
• 分子名称: Nicotinamide phosphoribosyltransferase, PHOSPHATE ION, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: transferase
• 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: 114236.92

構造登録者

Oh, A.,Coons, M.,Brillantes, B.,Wang, W. (登録日: 2013-12-15, 公開日: 2014-10-22, 最終更新日: 2024-02-28)

主引用文献

Wang, W.,Elkins, K.,Oh, A.,Ho, Y.C.,Wu, J.,Li, H.,Xiao, Y.,Kwong, M.,Coons, M.,Brillantes, B.,Cheng, E.,Crocker, L.,Dragovich, P.S.,Sampath, D.,Zheng, X.,Bair, K.W.,O'Brien, T.,Belmont, L.D.
Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors.
Plos One, 9:e109366-e109366, 2014

PubMed Abstract: Inhibiting NAD biosynthesis by blocking the function of nicotinamide phosphoribosyl transferase (NAMPT) is an attractive therapeutic strategy for targeting tumor metabolism. However, the development of drug resistance commonly limits the efficacy of cancer therapeutics. This study identifies mutations in NAMPT that confer resistance to a novel NAMPT inhibitor, GNE-618, in cell culture and in vivo, thus demonstrating that the cytotoxicity of GNE-618 is on target. We determine the crystal structures of six NAMPT mutants in the apo form and in complex with various inhibitors and use cellular, biochemical and structural data to elucidate two resistance mechanisms. One is the surprising finding of allosteric modulation by mutation of residue Ser165, resulting in unwinding of an α-helix that binds the NAMPT substrate 5-phosphoribosyl-1-pyrophosphate (PRPP). The other mechanism is orthosteric blocking of inhibitor binding by mutations of Gly217. Furthermore, by evaluating a panel of diverse small molecule inhibitors, we unravel inhibitor structure activity relationships on the mutant enzymes. These results provide valuable insights into the design of next generation NAMPT inhibitors that offer improved therapeutic potential by evading certain mechanisms of resistance.

PubMed: 25285661
DOI: 10.1371/journal.pone.0109366

実験手法

X-RAY DIFFRACTION (2.092 Å)