Structural basis for the recognition of peptide RJPXD33 by acyltransferases in lipid A biosynthesis.
J Biol Chem
; 289(22): 15527-35, 2014 May 30.
Article
em En
| MEDLINE
| ID: mdl-24742680
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)-ß-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.
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Base de dados:
MEDLINE
Assunto principal:
Peptídeos
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Aciltransferases
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Proteínas de Escherichia coli
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Escherichia coli
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Lipídeo A
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article