2JJY

Crystal structure of Francisella tularensis enoyl reductase (ftFabI) with bound NAD

2JJY の概要

• エントリーDOI: 10.2210/pdb2jjy/pdb
• 分子名称: ENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE, NICOTINAMIDE-ADENINE-DINUCLEOTIDE (2 entities in total)
• 機能のキーワード: oxidoreductase, fatty acid biosynthesis
• 由来する生物種: FRANCISELLA TULARENSIS
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 116288.82

構造登録者

Luckner, S.R.,Lu, H.,Truglio, J.J.,Tonge, P.J.,Kisker, C. (登録日: 2008-04-25, 公開日: 2009-02-24, 最終更新日: 2024-05-08)

主引用文献

Lu, H.,England, K.,Am Ende, C.,Truglio, J.J.,Luckner, S.R.,Marlenee, N.,Knudson, S.E.,Knudson, D.L.,Bowen, R.A.,Kisker, C.,Slayden, R.A.,Tonge, P.J.
Slow-Onset Inhibition of the Fabi Enoyl Reductase from Francisella Tularensis: Residence Time and in Vivo Activity
Acs Chem.Biol., 4:221-, 2009

PubMed Abstract: Francisella tularensis is a highly virulent and contagious Gram-negative intracellular bacterium that causes the disease tularemia in mammals. The high infectivity and the ability of the bacterium to survive for weeks in a cool, moist environment have raised the possibility that this organism could be exploited deliberately as a potential biological weapon. Fatty acid biosynthesis (FAS-II) is essential for bacterial viability and has been validated as a target for the discovery of novel antibacterials. The FAS-II enoyl reductase ftuFabI has been cloned and expressed, and a series of diphenyl ethers have been identified that are subnanomolar inhibitors of the enzyme with MIC90 values as low as 0.00018 microg mL(-1). The existence of a linear correlation between the Ki and MIC values strongly suggests that the antibacterial activity of the diphenyl ethers results from direct inhibition of ftuFabI within the cell. The compounds are slow-onset inhibitors of ftuFabI, and the residence time of the inhibitors on the enzyme correlates with their in vivo activity in a mouse model of tularemia infection. Significantly, the rate of breakdown of the enzyme-inhibitor complex is a better predictor of in vivo activity than the overall thermodynamic stability of the complex, a concept that has important implications for the discovery of novel chemotherapeutics that normally rely on equilibrium measurements of potency.

PubMed: 19206187
DOI: 10.1021/CB800306Y

実験手法

X-RAY DIFFRACTION (2.9 Å)