4C13: x-ray crystal structure of Staphylococcus aureus MurE with UDP-MurNAc- Ala-Glu-Lys

Formation of the peptidoglycan stem pentapeptide requires the insertion of both L and D amino acids by the ATP-dependent ligase enzymes MurC, -D, -E, and -F. The stereochemical control of the third position amino acid in the pentapeptide is crucial to maintain the fidelity of later biosynthetic steps contributing to cell morphology, antibiotic resistance, and pathogenesis. Here we determined the x-ray crystal structure of Staphylococcus aureus MurE UDP-N-acetylmuramoyl-L-alanyl-D-glutamate:meso-2,6-diaminopimelate ligase (MurE) (E.C. at 1.8 A resolution in the presence of ADP and the reaction product, UDP-MurNAc-L-Ala-gamma-D-Glu-L-Lys. This structure provides for the first time a molecular understanding of how this Gram-positive enzyme discriminates between L-lysine and D,L-diaminopimelic acid, the predominant amino acid that replaces L-lysine in Gram-negative peptidoglycan. Despite the presence of a consensus sequence previously implicated in the selection of the third position residue in the stem pentapeptide in S. aureus MurE, the structure shows that only part of this sequence is involved in the selection of L-lysine. Instead, other parts of the protein contribute substrate-selecting residues, resulting in a lysine-binding pocket based on charge characteristics. Despite the absolute specificity for L-lysine, S. aureus MurE binds this substrate relatively poorly. In vivo analysis and metabolomic data reveal that this is compensated for by high cytoplasmic L-lysine concentrations. Therefore, both metabolic and structural constraints maintain the structural integrity of the staphylococcal peptidoglycan. This study provides a novel focus for S. aureus-directed antimicrobials based on dual targeting of essential amino acid biogenesis and its linkage to cell wall assembly.
PDB ID: 4C13Download
MMDB ID: 114185
PDB Deposition Date: 2013/8/9
Updated in MMDB: 2013/11
Experimental Method:
x-ray diffraction
Resolution: 1.9  Å
Source Organism:
Similar Structures:
Biological Unit for 4C13: dimeric; determined by author and by software (PISA)
Molecular Components in 4C13
Label Count Molecule
Proteins (2 molecules)
Udp-n-acetylmuramoyl-l-alanyl-d-glutamate--l-lysine Ligase
Molecule annotation
Chemicals (12 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB