Structure of UDP-N-acetylglucosamine acyltransferase with a bound antibacterial pentadecapeptide

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Abstract
UDP-GlcNAc acyltransferase (LpxA) catalyzes the first step of lipid A biosynthesis, the transfer of theR-3-hydroxyacyl chain fromR-3-hydroxyacyl acyl carrier protein (ACP) to the glucosamine 3-OH group of UDP-GlcNAc. LpxA is essential for the growth ofEscherichia coliand related Gram-negative bacteria. The crystal structure of theE. coliLpxA homotrimer, determined previously at 2.6 Å in the absence of substrates or inhibitors, revealed that LpxA contains an unusual, left-handed parallel β-helix fold. We now present the crystal structure at 1.8 Å resolution ofE. coliLpxA in a complex with a pentadecapeptide, peptide 920. Three peptides, each of which adopts a β-hairpin conformation, are bound per LpxA trimer. The peptides are located at the interfaces of adjacent subunits in the vicinity of the three active sites. Each peptide interacts with residues from both adjacent subunits. Peptide 920 is a potent inhibitor ofE. coliLpxA (Ki= 50 nM). It is competitive with respect to acyl-ACP but not UDP-GlcNAc. The compact β-turn structure of peptide 920 bound to LpxA may open previously uncharacterized approaches to the rational design of LpxA inhibitors with antibiotic activity.