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'''Structure of E. coli FabF (KASII) C163Q mutant''' | '''Structure of E. coli FabF (KASII) C163Q mutant''' | ||
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[[Category: Parthasarathy, G]] | [[Category: Parthasarathy, G]] | ||
[[Category: Soisson, S M.]] | [[Category: Soisson, S M.]] | ||
[[Category: | [[Category: Acyl-enzyme intermediate]] | ||
[[Category: | [[Category: Fabf]] | ||
[[Category: | [[Category: Kasii]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 05:03:38 2008'' | |||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | |||
Revision as of 05:03, 4 May 2008
Structure of E. coli FabF (KASII) C163Q mutant
OverviewOverview
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.
About this StructureAbout this Structure
2GFV is a Single protein structure of sequence from Escherichia coli. Full crystallographic information is available from OCA.
ReferenceReference
Platensimycin is a selective FabF inhibitor with potent antibiotic properties., Wang J, Soisson SM, Young K, Shoop W, Kodali S, Galgoci A, Painter R, Parthasarathy G, Tang YS, Cummings R, Ha S, Dorso K, Motyl M, Jayasuriya H, Ondeyka J, Herath K, Zhang C, Hernandez L, Allocco J, Basilio A, Tormo JR, Genilloud O, Vicente F, Pelaez F, Colwell L, Lee SH, Michael B, Felcetto T, Gill C, Silver LL, Hermes JD, Bartizal K, Barrett J, Schmatz D, Becker JW, Cully D, Singh SB, Nature. 2006 May 18;441(7091):358-61. PMID:16710421 Page seeded by OCA on Sun May 4 05:03:38 2008