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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

1
From the Department of Medicinal Chemistry, College of Pharmacy, and.
2
Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109.
3
From the Department of Medicinal Chemistry, College of Pharmacy, and gdotson@umich.edu.

Abstract

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.

KEYWORDS:

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

PMID:
24742680
PMCID:
PMC4140908
DOI:
10.1074/jbc.M114.564278
[Indexed for MEDLINE]
Free PMC Article

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