Structural insight into the transglycosylation step of bacterial cell-wall biosynthesis.
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.
Lovering
Andrew L
AL
Department of Biochemistry and Molecular Biology, and Center for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, Canada.
de Castro
Liza H
LH
Lim
Daniel
D
Strynadka
Natalie C J
NC
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019881:Aminoacyltransferases / Q000737:chemistry* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism; D001051:Apoenzymes / Q000737:chemistry; D001665:Binding Sites; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D020134:Catalytic Domain; D002473:Cell Wall / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006031:Glycosylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000737:chemistry / Q000378:metabolism; D009844:Oligosaccharides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D046915:Penicillin-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D010457:Peptidoglycan / Q000096:biosynthesis*; D046928:Peptidoglycan Glycosyltransferase / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D013211:Staphylococcus aureus / Q000201:enzymology* / Q000378:metabolism
D000900:Anti-Bacterial Agents; D001051:Apoenzymes; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D009844:Oligosaccharides; D046915:Penicillin-Binding Proteins; D010457:Peptidoglycan; D019881:Aminoacyltransferases; C022330:peptidoglycan transpeptidase; D046928:Peptidoglycan Glycosyltransferase; C419802:moenomycin