Structure of the bacterial deacetylase LpxC bound to the nucleotide reaction product reveals mechanisms of oxyanion stabilization and proton transfer.

Abstract

The emergence of antibiotic-resistant strains of pathogenic bacteria is an increasing threat to global health that underscores an urgent need for an expanded antibacterial armamentarium. Gram-negative bacteria, such as Escherichia coli, have become increasingly important clinical pathogens with limited treatment options. This is due in part to their lipopolysaccharide (LPS) outer membrane components, which dually serve as endotoxins while also protecting Gram-negative bacteria from antibiotic entry. The LpxC enzyme catalyzes the committed step of LPS biosynthesis, making LpxC a promising target for new antibacterials. Here, we present the first structure of an LpxC enzyme in complex with the deacetylation reaction product, UDP-(3-O-(R-3-hydroxymyristoyl))-glucosamine. These studies provide valuable insight into recognition of substrates and products by LpxC and a platform for structure-guided drug discovery of broad spectrum Gram-negative antibiotics.

DOI: 10.1074/jbc.M113.513028

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Cite this paper

@article{Clayton2013StructureOT, title={Structure of the bacterial deacetylase LpxC bound to the nucleotide reaction product reveals mechanisms of oxyanion stabilization and proton transfer.}, author={Gina M Clayton and Daniel J. Klein and Keith W Rickert and Sangita B Patel and Maria Kornienko and Joan Zugay-Murphy and John C. Reid and Srivanya Tummala and Sujata Sharma and Sheo Baran Singh and Lynn Miesel and Kevin J Lumb and Stephen M. Soisson}, journal={The Journal of biological chemistry}, year={2013}, volume={288 47}, pages={34073-80} }