1fj4
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(New page: 200px<br /><applet load="1fj4" size="450" color="white" frame="true" align="right" spinBox="true" caption="1fj4, resolution 2.35Å" /> '''THE STRUCTURE OF BET...)
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Revision as of 12:50, 20 November 2007
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THE STRUCTURE OF BETA-KETOACYL-[ACYL CARRIER PROTEIN] SYNTHASE I IN COMPLEX WITH THIOLACTOMYCIN, IMPLICATIONS FOR DRUG DESIGN
Overview
The beta-ketoacyl-acyl carrier protein (ACP) synthases are key regulators, of type II fatty acid synthesis and are the targets for two natural, products, thiolactomycin (TLM) and cerulenin. The high resolution, structures of the FabB-TLM and FabB-cerulenin binary complexes were, determined. TLM mimics malonyl-ACP in the FabB active site. It forms, strong hydrogen bond interactions with the two catalytic histidines, and, the unsaturated alkyl side chain interaction with a small hydrophobic, pocket is stabilized by pi stacking interactions. Cerulenin binding mimics, the condensation transition state. The subtle differences between the, FabB-cerulenin and FabF-cerulenin (Moche, M., Schneider, G., Edwards, P., Dehesh, K., and Lindqvist, Y. (1999) J. Biol. Chem. 244, 6031-6034), structures explain the differences in the sensitivity of the two enzymes, to the antibiotic and may reflect the distinct substrate specificities, that differentiate the two enzymes. The FabB[H333N] protein was prepared, to convert the FabB His-His-Cys active site triad into the FabH, His-Asn-Cys configuration to test the importance of the two His residues, in TLM and cerulenin binding. FabB[H333N] was significantly more resistant, to both antibiotics than FabB and had an affinity for TLM an order of, magnitude less than the wild-type enzyme, illustrating that the, two-histidine active site architecture is critical to protein-antibiotic, interaction. These data provide a structural framework for understanding, antibiotic sensitivity within this group of enzymes.
About this Structure
1FJ4 is a Single protein structure of sequence from Escherichia coli with TLM as ligand. Active as Beta-ketoacyl-acyl-carrier-protein synthase I, with EC number 2.3.1.41 Full crystallographic information is available from OCA.
Reference
Inhibition of beta-ketoacyl-acyl carrier protein synthases by thiolactomycin and cerulenin. Structure and mechanism., Price AC, Choi KH, Heath RJ, Li Z, White SW, Rock CO, J Biol Chem. 2001 Mar 2;276(9):6551-9. Epub 2000 Oct 24. PMID:11050088
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