1ehi
From Proteopedia
(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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| - | [[Image:1ehi.jpg|left|200px]]<br /><applet load="1ehi" size=" | + | [[Image:1ehi.jpg|left|200px]]<br /><applet load="1ehi" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1ehi, resolution 2.38Å" /> | caption="1ehi, resolution 2.38Å" /> | ||
'''D-ALANINE:D-LACTATE LIGASE (LMDDL2) OF VANCOMYCIN-RESISTANT LEUCONOSTOC MESENTEROIDES'''<br /> | '''D-ALANINE:D-LACTATE LIGASE (LMDDL2) OF VANCOMYCIN-RESISTANT LEUCONOSTOC MESENTEROIDES'''<br /> | ||
==Overview== | ==Overview== | ||
| - | BACKGROUND: The bacterial cell wall and the enzymes that synthesize it are | + | 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== | ==About this Structure== | ||
| - | 1EHI is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Leuconostoc_mesenteroides Leuconostoc mesenteroides] with MG, ADP and PHY as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/D-alanine--D-alanine_ligase D-alanine--D-alanine ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.2.4 6.3.2.4] Full crystallographic information is available from [http:// | + | 1EHI is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Leuconostoc_mesenteroides Leuconostoc mesenteroides] with <scene name='pdbligand=MG:'>MG</scene>, <scene name='pdbligand=ADP:'>ADP</scene> and <scene name='pdbligand=PHY:'>PHY</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/D-alanine--D-alanine_ligase D-alanine--D-alanine ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.2.4 6.3.2.4] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EHI OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Leuconostoc mesenteroides]] | [[Category: Leuconostoc mesenteroides]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Healy, V | + | [[Category: Healy, V L.]] |
[[Category: Jorczak-Baillass, J.]] | [[Category: Jorczak-Baillass, J.]] | ||
| - | [[Category: Knox, J | + | [[Category: Knox, J R.]] |
| - | [[Category: Kuzin, A | + | [[Category: Kuzin, A P.]] |
[[Category: Sun, T.]] | [[Category: Sun, T.]] | ||
| - | [[Category: Walsh, C | + | [[Category: Walsh, C T.]] |
[[Category: ADP]] | [[Category: ADP]] | ||
[[Category: MG]] | [[Category: MG]] | ||
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[[Category: atp-binding. grasp motif for atp.]] | [[Category: atp-binding. grasp motif for atp.]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:27:50 2008'' |
Revision as of 10:27, 21 February 2008
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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 , and 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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