4c12: Difference between revisions
New page: '''Unreleased structure''' The entry 4c12 is ON HOLD Authors: Fulop, V., Roper, D.I., Ruane, K.M., Barreteau, H., Boniface, A., Dementin, S., Blanot, D., Mengin-Lecreulx, D., Gobec, S.,... |
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The | ==X-ray Crystal Structure of Staphylococcus aureus MurE with UDP-MurNAc- Ala-Glu-Lys and ADP== | ||
<StructureSection load='4c12' size='340' side='right'caption='[[4c12]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4c12]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4C12 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4C12 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=KCX:LYSINE+NZ-CARBOXYLIC+ACID'>KCX</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=UML:URIDINE+5DIPHOSPHO+N-ACETYL+MURAMOYL-L-ALANYL-D-GLUTAMYL-L-LYSINE'>UML</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4c12 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c12 OCA], [https://pdbe.org/4c12 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4c12 RCSB], [https://www.ebi.ac.uk/pdbsum/4c12 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4c12 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/MURE_STAA8 MURE_STAA8] Catalyzes the addition of L-lysine to the nucleotide precursor UDP-N-acetylmuramoyl-L-alanyl-D-glutamate (UMAG) in the biosynthesis of bacterial cell-wall peptidoglycan. Can not use diaminopimelate as substrate. Seems to have a role in beta-lactam antibiotic resistance.<ref>PMID:14114846</ref> <ref>PMID:10498701</ref> <ref>PMID:14996801</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Formation of the peptidoglycan stem pentapeptide requires the insertion of both L or D amino acids by the ATP dependent ligase enzymes MurC, D, E and F. The stereo chemical 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 determine the X-ray crystal structure of Staphylococcus aureus MurE UDP-N-acetylmuramoyl-l-alanyl-d-glutamate: meso-2,6-diaminopimelate ligase (MurE) (E.C. 6.3.2.15) at 1.8 angstrom 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 reveals 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. | |||
Specificity Determinants for Lysine Incorporation in Staphylococcus aureus Peptidoglycan as Revealed by the Structure of a MurE Ternary Complex.,Ruane KM, Lloyd AJ, Fulop V, Dowson CG, Barreteau H, Boniface A, Dementin S, Blanot D, Mengin-Lecreulx D, Gobec S, Dessen A, Roper DI J Biol Chem. 2013 Sep 24. PMID:24064214<ref>PMID:24064214</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4c12" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Mur ligase|Mur ligase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Staphylococcus aureus]] | |||
[[Category: Barreteau H]] | |||
[[Category: Blanot D]] | |||
[[Category: Boniface A]] | |||
[[Category: Dementin S]] | |||
[[Category: Dessen A]] | |||
[[Category: Dowson CG]] | |||
[[Category: Fulop V]] | |||
[[Category: Gobec S]] | |||
[[Category: Lloyd AJ]] | |||
[[Category: Mengin-Lecreulx D]] | |||
[[Category: Roper DI]] | |||
[[Category: Ruane KM]] | |||
Latest revision as of 15:01, 20 December 2023
X-ray Crystal Structure of Staphylococcus aureus MurE with UDP-MurNAc- Ala-Glu-Lys and ADPX-ray Crystal Structure of Staphylococcus aureus MurE with UDP-MurNAc- Ala-Glu-Lys and ADP
Structural highlights
FunctionMURE_STAA8 Catalyzes the addition of L-lysine to the nucleotide precursor UDP-N-acetylmuramoyl-L-alanyl-D-glutamate (UMAG) in the biosynthesis of bacterial cell-wall peptidoglycan. Can not use diaminopimelate as substrate. Seems to have a role in beta-lactam antibiotic resistance.[1] [2] [3] Publication Abstract from PubMedFormation of the peptidoglycan stem pentapeptide requires the insertion of both L or D amino acids by the ATP dependent ligase enzymes MurC, D, E and F. The stereo chemical 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 determine the X-ray crystal structure of Staphylococcus aureus MurE UDP-N-acetylmuramoyl-l-alanyl-d-glutamate: meso-2,6-diaminopimelate ligase (MurE) (E.C. 6.3.2.15) at 1.8 angstrom 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 reveals 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. Specificity Determinants for Lysine Incorporation in Staphylococcus aureus Peptidoglycan as Revealed by the Structure of a MurE Ternary Complex.,Ruane KM, Lloyd AJ, Fulop V, Dowson CG, Barreteau H, Boniface A, Dementin S, Blanot D, Mengin-Lecreulx D, Gobec S, Dessen A, Roper DI J Biol Chem. 2013 Sep 24. PMID:24064214[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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