4C12

X-ray Crystal Structure of Staphylococcus aureus MurE with UDP-MurNAc- Ala-Glu-Lys and ADP

Summary for 4C12

• Entry DOI: 10.2210/pdb4c12/pdb
• Related: 4C13
• Related PRD ID: PRD_002099
• Descriptor: UDP-N-ACETYLMURAMOYL-L-ALANYL-D-GLUTAMATE--L-LYSINE LIGASE, GLYCEROL, Uridine 5'Diphospho N-acetyl muramoyl-L-Alanyl-D-Glutamyl-L-Lysine, ... (6 entities in total)
• Functional Keywords: ligase
• Biological source: STAPHYLOCOCCUS AUREUS
• Cellular location: Cytoplasm (By similarity): Q2FZP6
• Total number of polymer chains: 1
• Total formula weight: 56950.25

Authors

Fulop, V.,Roper, D.I.,Ruane, K.M.,Barreteau, H.,Boniface, A.,Dementin, S.,Blanot, D.,Mengin-Lecreulx, D.,Gobec, S.,Dessen, A.,Dowson, C.G.,Lloyd, A.J. (deposition date: 2013-08-09, release date: 2013-10-02, Last modification date: 2023-12-20)

Primary citation

Ruane, K.M.,Lloyd, A.J.,Fulop, V.,Dowson, C.G.,Barreteau, H.,Boniface, A.,Dementin, S.,Blanot, D.,Mengin-Lecreulx, D.,Gobec, S.,Dessen, A.,Roper, D.I.
Specificity Determinants for Lysine Incorporation in Staphylococcus Aureus Peptidoglycan as Revealed by the Structure of a Mure Enzyme Ternary Complex.
J.Biol.Chem., 288:33439-, 2013

PubMed Abstract: 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. 6.3.2.7) at 1.8 Å resolution in the presence of ADP and the reaction product, UDP-MurNAc-L-Ala-γ-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.

PubMed: 24064214
DOI: 10.1074/JBC.M113.508135

Experimental method

X-RAY DIFFRACTION (1.8 Å)