4fu0 | pdb_00004fu0

Crystal Structure of VanG D-Ala:D-Ser Ligase from Enterococcus faecalis

spinqualitylabelsall models 4fu0, resolution 2.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4fu0 is a 2 chain structure with sequence from "enterococcus_proteiformis"_thiercelin_and_jouhaud_1903 "enterococcus proteiformis" thiercelin and jouhaud 1903. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ADP, SO4 Gene: ddl7, vanG ("Enterococcus proteiformis" Thiercelin and Jouhaud 1903) Activity: D-alanine--D-alanine ligase, with EC number 6.3.2.4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [Q6WRY5_ENTFL] Cell wall formation.[HAMAP-Rule:MF_00047][SAAS:SAAS00083922] Publication Abstract from PubMed d-Alanyl:d-lactate (d-Ala:d-Lac) and d-alanyl:d-serine ligases are key enzymes in vancomycin resistance of Gram-positive cocci. They catalyze a critical step in the synthesis of modified peptidoglycan precursors that are low binding affinity targets for vancomycin. The structure of the d-Ala:d-Lac ligase VanA led to the understanding of the molecular basis for its specificity, but that of d-Ala:d-Ser ligases had not been determined. We have investigated the enzymatic kinetics of the d-Ala:d-Ser ligase VanG from Enterococcus faecalis and solved its crystal structure in complex with ADP. The overall structure of VanG is similar to that of VanA but has significant differences mainly in the N-terminal and central domains. Based on reported mutagenesis data and comparison of the VanG and VanA structures, we show that residues Asp-243, Phe-252, and Arg-324 are molecular determinants for d-Ser selectivity. These residues are conserved in both enzymes and explain why VanA also displays d-Ala:d-Ser ligase activity, albeit with low catalytic efficiency in comparison with VanG. These observations suggest that d-Ala:d-Lac and d-Ala:d-Ser enzymes have evolved from a common ancestral d-Ala:d-X ligase. The crystal structure of VanG showed an unusual interaction between two dimers involving residues of the omega loop that are deeply anchored in the active site. We constructed an octapeptide mimicking the omega loop and found that it selectively inhibits VanG and VanA but not Staphylococcus aureus d-Ala:d-Ala ligase. This study provides additional insight into the molecular evolution of d-Ala:d-X ligases and could contribute to the development of new structure-based inhibitors of vancomycin resistance enzymes. Structural and functional characterization of VanG D-Ala:D-Ser ligase associated with vancomycin resistance in Enterococcus faecalis.,Meziane-Cherif D, Saul FA, Haouz A, Courvalin P J Biol Chem. 2012 Nov 2;287(45):37583-92. doi: 10.1074/jbc.M112.405522. Epub 2012, Sep 11. PMID:22969085 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also D-alanine-D-alanine ligase

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