5ENZ

S. aureus MnaA-UDP co-structure


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.91 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.205 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Chemical Genetic Analysis and Functional Characterization of Staphylococcal Wall Teichoic Acid 2-Epimerases Reveals Unconventional Antibiotic Drug Targets.

Mann, P.A.Muller, A.Wolff, K.A.Fischmann, T.Wang, H.Reed, P.Hou, Y.Li, W.Muller, C.E.Xiao, J.Murgolo, N.Sher, X.Mayhood, T.Sheth, P.R.Mirza, A.Labroli, M.Xiao, L.McCoy, M.Gill, C.J.Pinho, M.G.Schneider, T.Roemer, T.

(2016) PLoS Pathog 12: e1005585-e1005585

  • DOI: https://doi.org/10.1371/journal.ppat.1005585
  • Primary Citation of Related Structures:  
    5ENZ

  • PubMed Abstract: 

    Here we describe a chemical biology strategy performed in Staphylococcus aureus and Staphylococcus epidermidis to identify MnaA, a 2-epimerase that we demonstrate interconverts UDP-GlcNAc and UDP-ManNAc to modulate substrate levels of TarO and TarA wall teichoic acid (WTA) biosynthesis enzymes. Genetic inactivation of mnaA results in complete loss of WTA and dramatic in vitro β-lactam hypersensitivity in methicillin-resistant S. aureus (MRSA) and S. epidermidis (MRSE). Likewise, the β-lactam antibiotic imipenem exhibits restored bactericidal activity against mnaA mutants in vitro and concomitant efficacy against 2-epimerase defective strains in a mouse thigh model of MRSA and MRSE infection. Interestingly, whereas MnaA serves as the sole 2-epimerase required for WTA biosynthesis in S. epidermidis, MnaA and Cap5P provide compensatory WTA functional roles in S. aureus. We also demonstrate that MnaA and other enzymes of WTA biosynthesis are required for biofilm formation in MRSA and MRSE. We further determine the 1.9Å crystal structure of S. aureus MnaA and identify critical residues for enzymatic dimerization, stability, and substrate binding. Finally, the natural product antibiotic tunicamycin is shown to physically bind MnaA and Cap5P and inhibit 2-epimerase activity, demonstrating that it inhibits a previously unanticipated step in WTA biosynthesis. In summary, MnaA serves as a new Staphylococcal antibiotic target with cognate inhibitors predicted to possess dual therapeutic benefit: as combination agents to restore β-lactam efficacy against MRSA and MRSE and as non-bioactive prophylactic agents to prevent Staphylococcal biofilm formation.


  • Organizational Affiliation

    Merck Research Laboratories, Kenilworth New Jersey, United States of America.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
UDP-GlcNAc 2-epimerase
A, B
385Staphylococcus aureusMutation(s): 0 
Gene Names: 
EC: 5.1.3.14
UniProt
Find proteins for Q9REV4 (Staphylococcus aureus)
Explore Q9REV4 
Go to UniProtKB:  Q9REV4
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9REV4
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
UDP
Query on UDP

Download Ideal Coordinates CCD File 
C [auth A],
G [auth B]
URIDINE-5'-DIPHOSPHATE
C9 H14 N2 O12 P2
XCCTYIAWTASOJW-XVFCMESISA-N
PG4
Query on PG4

Download Ideal Coordinates CCD File 
F [auth A]TETRAETHYLENE GLYCOL
C8 H18 O5
UWHCKJMYHZGTIT-UHFFFAOYSA-N
TRS
Query on TRS

Download Ideal Coordinates CCD File 
E [auth A],
K [auth B]
2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL
C4 H12 N O3
LENZDBCJOHFCAS-UHFFFAOYSA-O
SO4
Query on SO4

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

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.91 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.205 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 54.19α = 90
b = 82.78β = 90
c = 170.88γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
Aimlessdata scaling
MOLREPphasing
PDB_EXTRACTdata extraction
PHENIXmodel building
XDSdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-04-27
    Type: Initial release
  • Version 1.1: 2016-05-18
    Changes: Database references
  • Version 1.2: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description