2GFX

Structure of E. coli FabF(C163Q) in complex with Platensimycin

2GFX の概要

• エントリーDOI: 10.2210/pdb2gfx/pdb
• 関連するPDBエントリー: 2GFV 2GFW 2GFY
• 分子名称: 3-oxoacyl-[acyl-carrier-protein] synthase 2, PLATENSIMYCIN (3 entities in total)
• 機能のキーワード: fabf; kasii; ketoacyl synthase; platensimycin, transferase
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 45103.76

構造登録者

Soisson, S.M.,Parthasarathy, G. (登録日: 2006-03-23, 公開日: 2006-05-23, 最終更新日: 2024-02-14)

主引用文献

Wang, J.,Soisson, S.M.,Young, K.,Shoop, W.,Kodali, S.,Galgoci, A.,Painter, R.,Parthasarathy, G.,Tang, Y.S.,Cummings, R.,Ha, S.,Dorso, K.,Motyl, M.,Jayasuriya, H.,Ondeyka, J.,Herath, K.,Zhang, C.,Hernandez, L.,Allocco, J.,Basilio, A.,Tormo, J.R.,Genilloud, O.,Vicente, F.,Pelaez, F.,Colwell, L.,Lee, S.H.,Michael, B.,Felcetto, T.,Gill, C.,Silver, L.L.,Hermes, J.D.,Bartizal, K.,Barrett, J.,Schmatz, D.,Becker, J.W.,Cully, D.,Singh, S.B.
Platensimycin is a selective FabF inhibitor with potent antibiotic properties.
Nature, 441:358-361, 2006

PubMed Abstract: Bacterial infection remains a serious threat to human lives because of emerging resistance to existing antibiotics. Although the scientific community has avidly pursued the discovery of new antibiotics that interact with new targets, these efforts have met with limited success since the early 1960s. Here we report the discovery of platensimycin, a previously unknown class of antibiotics produced by Streptomyces platensis. Platensimycin demonstrates strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis. We show that this anti-bacterial effect is exerted through the selective targeting of beta-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B) in the synthetic pathway of fatty acids. Direct binding assays show that platensimycin interacts specifically with the acyl-enzyme intermediate of the target protein, and X-ray crystallographic studies reveal that a specific conformational change that occurs on acylation must take place before the inhibitor can bind. Treatment with platensimycin eradicates Staphylococcus aureus infection in mice. Because of its unique mode of action, platensimycin shows no cross-resistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant enterococci. Platensimycin is the most potent inhibitor reported for the FabF/B condensing enzymes, and is the only inhibitor of these targets that shows broad-spectrum activity, in vivo efficacy and no observed toxicity.

PubMed: 16710421
DOI: 10.1038/nature04784

実験手法

X-RAY DIFFRACTION (2.59 Å)