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| The EMBO Journal
(2000) 19, 5281–5287, doi:10.1093/emboj/19.20.5281 |
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| Crystal structure of Streptococcus pneumoniae acyl carrier protein synthase: an essential enzyme in bacterial fatty acid biosynthesis |
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| Nickolay Y. Chirgadze, Steven L. Briggs, Kelly A. McAllister, Anthony S. Fischl and Genshi Zhao |
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Lilly Research Laboratories, Indianapolis, IN 46285, USA To whom correspondence should be addressed Nickolay Y. Chirgadze, nyc@lilly.com Received 24 July 2000; Revised 29 August 2000; Accepted 30 August 2000. |
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| Abstract |
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Acyl carrier protein synthase (AcpS) catalyzes the formation of holo-ACP, which mediates the essential transfer of acyl fatty acid intermediates during the biosynthesis of fatty acids and lipids in the cell. Thus, AcpS plays an important role in bacterial fatty acid and lipid biosynthesis, making it an attractive target for therapeutic intervention. We have determined, for the first time, the crystal structure of the Streptococcus pneumoniae AcpS and AcpS complexed with 3'5'-ADP, a product of AcpS, at 2.0 and 1.9 Å resolution, respectively. The crystal structure reveals an  / fold and shows that AcpS assembles as a tightly packed functional trimer, with a non-crystallographic pseudo-symmetric 3-fold axis, which contains three active sites at the interface between protomers. Only two active sites are occupied by the ligand molecules. Although there is virtually no sequence similarity between the S.pneumoniae AcpS and the Bacillus subtilis Sfp transferase, a striking structural similarity between both enzymes was observed. These data provide a starting point for structure-based drug design efforts towards the identification of AcpS inhibitors with potent antibacterial activity. |
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| Keywords: acyl carrier protein synthase, bacterial fatty acid biosynthesis, coenzyme A, structure-based drug design, X-ray crystallography |
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