Send to

Choose Destination
J Biol Chem. 2014 May 30;289(22):15527-35. doi: 10.1074/jbc.M114.564278. Epub 2014 Apr 16.

Structural basis for the recognition of peptide RJPXD33 by acyltransferases in lipid A biosynthesis.

Author information

From the Department of Medicinal Chemistry, College of Pharmacy, and.
Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109.
From the Department of Medicinal Chemistry, College of Pharmacy, and


UDP-N-acetylglucosamine acyltransferase (LpxA) and UDP-3-O-(acyl)-glucosamine acyltransferase (LpxD) constitute the essential, early acyltransferases of lipid A biosynthesis. Recently, an antimicrobial peptide inhibitor, RJPXD33, was identified with dual affinity for LpxA and LpxD. To gain a fundamental understanding of the molecular basis of inhibitor binding, we determined the crystal structure of LpxA from Escherichia coli in complex with RJPXD33 at 1.9 Å resolutions. Our results suggest that the peptide binds in a unique modality that mimics (R)-β-hydroxyacyl pantetheine binding to LpxA and displays how the peptide binds exclusive of the native substrate, acyl-acyl carrier protein. Acyltransferase binding studies with photo-labile RJPXD33 probes and truncations of RJPXD33 validated the structure and provided fundamental insights for future design of small molecule inhibitors. Overlay of the LpxA-RJPXD33 structure with E. coli LpxD identified a complementary peptide binding pocket within LpxD and serves as a model for further biochemical characterization of RJPXD33 binding to LpxD.


Acyl Carrier Protein (ACP); Acyltransferase; Antimicrobial Peptide (AMP); Enzyme Inhibitor; Lipid A; Lipopolysaccharide (LPS); LpxA; Peptides; X-ray Crystallography

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center