4CV3

Crystal structure of E. coli FabI in complex with NADH and PT166

4CV3 の概要

• エントリーDOI: 10.2210/pdb4cv3/pdb
• 関連するPDBエントリー: 4CUZ 4CV0 4CV1 4CV2
• 分子名称: ENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADH], 2-hexyl-1-methyl-5-(2-methylphenoxy)pyridin-4(1H)-one, 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE, ... (4 entities in total)
• 機能のキーワード: short-chain dehydrogenase/reductase superfamily, fatty acid biosynthesis, lipid synthesis, ecfabi, oxidoreductase
• 由来する生物種: ESCHERICHIA COLI
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 59857.83

構造登録者

Eltschkner, S.,Schiebel, J.,Chang, A.,Shah, S.,Tonge, P.J.,Kisker, C. (登録日: 2014-03-22, 公開日: 2014-04-16, 最終更新日: 2023-12-20)

主引用文献

Schiebel, J.,Chang, A.,Shah, S.,Lu, Y.,Liu, L.,Pan, P.,Hirschbeck, M.W.,Tareilus, M.,Eltschkner, S.,Yu, W.,Cummings, J.E.,Knudson, S.E.,Bommineni, G.R.,Walker, S.G.,Slayden, R.A.,Sotriffer, C.A.,Tonge, P.J.,Kisker, C.
Rational Design of Broad Spectrum Antibacterial Activity Based on a Clinically Relevant Enoyl-Acyl Carrier Protein (Acp) Reductase Inhibitor.
J.Biol.Chem., 289:15987-, 2014

PubMed Abstract: Determining the molecular basis for target selectivity is of particular importance in drug discovery. The ideal antibiotic should be active against a broad spectrum of pathogenic organisms with a minimal effect on human targets. CG400549, a Staphylococcus-specific 2-pyridone compound that inhibits the enoyl-acyl carrier protein reductase (FabI), has recently been shown to possess human efficacy for the treatment of methicillin-resistant Staphylococcus aureus infections, which constitute a serious threat to human health. In this study, we solved the structures of three different FabI homologues in complex with several pyridone inhibitors, including CG400549. Based on these structures, we rationalize the 65-fold reduced affinity of CG400549 toward Escherichia coli versus S. aureus FabI and implement concepts to improve the spectrum of antibacterial activity. The identification of different conformational states along the reaction coordinate of the enzymatic hydride transfer provides an elegant visual depiction of the relationship between catalysis and inhibition, which facilitates rational inhibitor design. Ultimately, we developed the novel 4-pyridone-based FabI inhibitor PT166 that retained favorable pharmacokinetics and efficacy in a mouse model of S. aureus infection with extended activity against Gram-negative and mycobacterial organisms.

PubMed: 24739388
DOI: 10.1074/JBC.M113.532804

実験手法

X-RAY DIFFRACTION (1.95 Å)