1ehi
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(New page: 200px<br /><applet load="1ehi" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ehi, resolution 2.38Å" /> '''D-ALANINE:D-LACTATE ...)
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Revision as of 20:09, 24 November 2007
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D-ALANINE:D-LACTATE LIGASE (LMDDL2) OF VANCOMYCIN-RESISTANT LEUCONOSTOC MESENTEROIDES
Overview
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.
About this Structure
1EHI is a Single protein structure of sequence from Leuconostoc mesenteroides with MG, ADP and PHY as ligands. Active as D-alanine--D-alanine ligase, with EC number 6.3.2.4 Full crystallographic information is available from OCA.
Reference
Enzymes of vancomycin resistance: the structure of D-alanine-D-lactate ligase of naturally resistant Leuconostoc mesenteroides., Kuzin AP, Sun T, Jorczak-Baillass J, Healy VL, Walsh CT, Knox JR, Structure. 2000 May 15;8(5):463-70. PMID:10801495
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