Structural insight into the transglycosylation step of bacterial cell-wall biosynthesis

Science. 2007 Mar 9;315(5817):1402-5. doi: 10.1126/science.1136611.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Aminoacyltransferases / chemistry*
  • Aminoacyltransferases / metabolism
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / metabolism
  • Apoenzymes / chemistry
  • Binding Sites
  • Carbohydrate Conformation
  • Carbohydrate Sequence
  • Catalytic Domain
  • Cell Wall / metabolism*
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Glycosylation
  • Models, Molecular
  • Molecular Sequence Data
  • Multienzyme Complexes / chemistry
  • Multienzyme Complexes / metabolism
  • Oligosaccharides / chemistry
  • Oligosaccharides / metabolism
  • Oligosaccharides / pharmacology
  • Penicillin-Binding Proteins / chemistry*
  • Penicillin-Binding Proteins / metabolism
  • Peptidoglycan / biosynthesis*
  • Peptidoglycan Glycosyltransferase / chemistry*
  • Peptidoglycan Glycosyltransferase / metabolism
  • Protein Conformation
  • Protein Folding
  • Protein Structure, Tertiary
  • Staphylococcus aureus / enzymology*
  • Staphylococcus aureus / metabolism

Substances

  • Anti-Bacterial Agents
  • Apoenzymes
  • Enzyme Inhibitors
  • Multienzyme Complexes
  • Oligosaccharides
  • Penicillin-Binding Proteins
  • Peptidoglycan
  • Aminoacyltransferases
  • peptidoglycan transpeptidase
  • Peptidoglycan Glycosyltransferase
  • moenomycin

Associated data

  • PDB/2OLU
  • PDB/2OLV