4FU0

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.35 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.190 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural and functional characterization of VanG D-Ala:D-Ser ligase associated with vancomycin resistance in Enterococcus faecalis

Meziane-Cherif, D.Saul, F.A.Haouz, A.Courvalin, P.

(2012) J Biol Chem 287: 37583-37592

  • DOI: https://doi.org/10.1074/jbc.M112.405522
  • Primary Citation of Related Structures:  
    4FU0

  • PubMed Abstract: 

    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.


  • Organizational Affiliation

    Institut Pasteur, Unité des Agents Antibactériens, Paris Cedex 15, France. djalal.meziane-cherif@pasteur.fr


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
D-alanine--D-alanine ligase 7
A, B
357Enterococcus faecalisMutation(s): 0 
Gene Names: ddl7vanG
EC: 6.3.2.4
UniProt
Find proteins for Q6WRY5 (Enterococcus faecalis)
Explore Q6WRY5 
Go to UniProtKB:  Q6WRY5
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ6WRY5
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ADP
Query on ADP

Download Ideal Coordinates CCD File 
C [auth A],
H [auth B]
ADENOSINE-5'-DIPHOSPHATE
C10 H15 N5 O10 P2
XTWYTFMLZFPYCI-KQYNXXCUSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
F [auth A]
G [auth A]
I [auth B]
D [auth A],
E [auth A],
F [auth A],
G [auth A],
I [auth B],
J [auth B],
K [auth B],
L [auth B],
M [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.35 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.190 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 116.07α = 90
b = 116.07β = 90
c = 177.228γ = 120
Software Package:
Software NamePurpose
ADSCdata collection
PHASERphasing
REFMACrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-09-19
    Type: Initial release
  • Version 1.1: 2013-03-13
    Changes: Database references
  • Version 1.2: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description