Abstract
Peptidoglycan glycosyltransferases (GTs) catalyze the polymerization step of cell-wall biosynthesis, are membrane-bound, and are highly conserved across all bacteria. Long considered the "holy grail" of antibiotic research, they represent an essential and easily accessible drug target for antibiotic-resistant bacteria, including methicillin-resistant Staphylococcus aureus. We have determined the 2.8 angstrom structure of a bifunctional cell-wall cross-linking enzyme, including its transpeptidase and GT domains, both unliganded and complexed with the substrate analog moenomycin. The peptidoglycan GTs adopt a fold distinct from those of other GT classes. The structures give insight into critical features of the catalytic mechanism and key interactions required for enzyme inhibition.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Motifs
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Amino Acid Sequence
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Aminoacyltransferases / chemistry*
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Aminoacyltransferases / metabolism
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / metabolism
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Apoenzymes / chemistry
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Binding Sites
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Carbohydrate Conformation
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Carbohydrate Sequence
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Catalytic Domain
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Cell Wall / metabolism*
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Crystallography, X-Ray
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology
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Glycosylation
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Models, Molecular
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Molecular Sequence Data
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Multienzyme Complexes / chemistry
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Multienzyme Complexes / metabolism
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Oligosaccharides / chemistry
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Oligosaccharides / metabolism
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Oligosaccharides / pharmacology
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Penicillin-Binding Proteins / chemistry*
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Penicillin-Binding Proteins / metabolism
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Peptidoglycan / biosynthesis*
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Peptidoglycan Glycosyltransferase / chemistry*
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Peptidoglycan Glycosyltransferase / metabolism
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Protein Conformation
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Protein Folding
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Protein Structure, Tertiary
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Staphylococcus aureus / enzymology*
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Staphylococcus aureus / metabolism
Substances
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Anti-Bacterial Agents
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Apoenzymes
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Enzyme Inhibitors
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Multienzyme Complexes
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Oligosaccharides
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Penicillin-Binding Proteins
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Peptidoglycan
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Aminoacyltransferases
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peptidoglycan transpeptidase
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Peptidoglycan Glycosyltransferase
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moenomycin