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PDBsum entry 1ehi

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Ligase PDB id
1ehi
Jmol
Contents
Protein chains
360 a.a. *
Ligands
ADP
PHY
Metals
_MG ×2
Waters ×213
* Residue conservation analysis

References listed in PDB file
Key reference
Title Enzymes of vancomycin resistance: the structure of d-Alanine-D-Lactate ligase of naturally resistant leuconostoc mesenteroides.
Authors A.P.Kuzin, T.Sun, J.Jorczak-Baillass, V.L.Healy, C.T.Walsh, J.R.Knox.
Ref. Structure, 2000, 8, 463-470. [DOI no: 10.1016/S0969-2126(00)00129-5]
PubMed id 10801495
Abstract
BACKGROUND: The bacterial cell wall and the enzymes that synthesize it are targets of glycopeptide antibiotics (vancomycins and teicoplanins) and beta-lactams (penicillins and cephalosporins). Biosynthesis of cell wall peptidoglycan requires a crosslinking of peptidyl moieties on adjacent glycan strands. The D-alanine-D-alanine transpeptidase, which catalyzes this crosslinking, is the target of beta-lactam antibiotics. Glycopeptides, in contrast, do not inhibit an enzyme, but bind directly to D-alanine-D-alanine and prevent subsequent crosslinking by the transpeptidase. Clinical resistance to vancomycin in enterococcal pathogens has been traced to altered ligases producing D-alanine-D-lactate rather than D-alanine-D-alanine. RESULTS: The structure of a D-alanine-D-lactate ligase has been determined by multiple anomalous dispersion (MAD) phasing to 2.4 A resolution. Co-crystallization of the Leuconostoc mesenteroides LmDdl2 ligase with ATP and a di-D-methylphosphinate produced ADP and a phosphinophosphate analog of the reaction intermediate of cell wall peptidoglycan biosynthesis. Comparison of this D-alanine-D-lactate ligase with the known structure of DdlB D-alanine-D-alanine ligase, a wild-type enzyme that does not provide vancomycin resistance, reveals alterations in the size and hydrophobicity of the site for D-lactate binding (subsite 2). A decrease was noted in the ability of the ligase to hydrogen bond a substrate molecule entering subsite 2. CONCLUSIONS: Structural differences at subsite 2 of the D-alanine-D-lactate ligase help explain a substrate specificity shift (D-alanine to D-lactate) leading to remodeled cell wall peptidoglycan and vancomycin resistance in Gram-positive pathogens.
Figure 6.
Figure 6. Schematic showing the distances listed in Table 2. Residues Tyr255, Lys260 and Phe261 are on the omega loop. Gly322NH and Arg301 form an oxyanion hole.
The above figure is reprinted by permission from Cell Press: Structure (2000, 8, 463-470) copyright 2000.
Secondary reference #1
Title Vancomycin resistance: structure of d-Alanine:d-Alanine ligase at 2.3 a resolution.
Authors C.Fan, P.C.Moews, C.T.Walsh, J.R.Knox.
Ref. Science, 1994, 266, 439-443. [DOI no: 10.1126/science.7939684]
PubMed id 7939684
Full text Abstract
Secondary reference #2
Title D-Alanine:d-Alanine ligase: phosphonate and phosphinate intermediates with wild type and the y216f mutant.
Authors C.Fan, I.S.Park, C.T.Walsh, J.R.Knox.
Ref. Biochemistry, 1997, 36, 2531-2538. [DOI no: 10.1021/bi962431t]
PubMed id 9054558
Full text Abstract
PROCHECK
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