title: The molecular basis of vancomycin resistance in clinically relevant Enterococci: crystal structure of D-alanyl-D-lactate ligase (VanA).
abstract: d-alanine-d-lactate ligase from Enterococcus faecium BM4147 is directly responsible for the biosynthesis of alternate cell-wall precursors in bacteria, which are resistant to the glycopeptide antibiotic vancomycin. The crystal structure has been determined with data extending to 2.5-A resolution. This structure shows that the active site has unexpected interactions and is distinct from previous models for d-alanyl-d-lactate ligase mechanistic studies. It appears that the preference of the enzyme for lactate as a ligand over d-alanine could be mediated by electrostatic effects and/or a hydrogen-bonding network, which principally involve His-244. The structure of d-alanyl-d-lactate ligase provides a revised interpretation of the molecular events that lead to vancomycin resistance.
authors.affiliation: York Structural Biology Laboratory, Department of Chemistry, The University of York, Heslington, York YO10 5DD, United Kingdom. roper@ysbl.york.ac.uk
authors.forename: D I
authors.initials: DI
authors.lastname: Roper
authors.forename: T
authors.initials: T
authors.lastname: Huyton
authors.forename: A
authors.initials: A
authors.lastname: Vagin
authors.forename: G
authors.initials: G
authors.lastname: Dodson
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry*; D019729:Carbon-Oxygen Ligases / Q000737:chemistry*; D018360:Crystallography, X-Ray; D016984:Enterococcus faecium / Q000187:drug effects*; D006860:Hydrogen Bonding; D011487:Protein Conformation; D020713:Vancomycin Resistance
chemical_list: D001426:Bacterial Proteins; C071437:VanA ligase, Bacteria; D019729:Carbon-Oxygen Ligases