1FJ4

THE STRUCTURE OF BETA-KETOACYL-[ACYL CARRIER PROTEIN] SYNTHASE I IN COMPLEX WITH THIOLACTOMYCIN, IMPLICATIONS FOR DRUG DESIGN

Summary for 1FJ4

• Entry DOI: 10.2210/pdb1fj4/pdb
• Related: 1B3N 1fj8
• Descriptor: BETA-KETOACYL-[ACYL CARRIER PROTEIN] SYNTHASE I, THIOLACTOMYCIN (3 entities in total)
• Functional Keywords: condensing enzymes, fatty acid elongation, thiolactomycin, drug design, transferase
• Biological source: Escherichia coli
• Cellular location: Cytoplasm: P0A953
• Total number of polymer chains: 4
• Total formula weight: 171465.98

Authors

Price, A.C.,Choi, K.,Heath, R.J.,Li, Z.,White, S.W.,Rock, C.O. (deposition date: 2000-08-07, release date: 2000-08-23, Last modification date: 2024-02-07)

Primary citation

Price, A.C.,Choi, K.H.,Heath, R.J.,Li, Z.,White, S.W.,Rock, C.O.
Inhibition of beta-ketoacyl-acyl carrier protein synthases by thiolactomycin and cerulenin. Structure and mechanism.
J.Biol.Chem., 276:6551-6559, 2001

PubMed Abstract: 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.

PubMed: 11050088
DOI: 10.1074/jbc.M007101200

Experimental method

X-RAY DIFFRACTION (2.35 Å)