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< | ==E. Cloacae MurA in complex with Enolpyruvyl-UNAG== | ||
<StructureSection load='3swq' size='340' side='right'caption='[[3swq]], [[Resolution|resolution]] 1.83Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3swq]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Enterobacter_cloacae_subsp._cloacae_ATCC_13047 Enterobacter cloacae subsp. cloacae ATCC 13047]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SWQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SWQ FirstGlance]. <br> | |||
or | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.83Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=EPU:URIDINE-DIPHOSPHATE-2(N-ACETYLGLUCOSAMINYL)+BUTYRIC+ACID'>EPU</scene>, <scene name='pdbligand=IAS:BETA-L-ASPARTIC+ACID'>IAS</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</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=3swq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3swq OCA], [https://pdbe.org/3swq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3swq RCSB], [https://www.ebi.ac.uk/pdbsum/3swq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3swq ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/MURA_ENTCC MURA_ENTCC] Cell wall formation. Adds enolpyruvyl to UDP-N-acetylglucosamine. Target for the antibiotic phosphomycin. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The enzyme MurA has been an established antibiotic target since the discovery of fosfomycin, which specifically inhibits MurA by covalent modification of the active site residue Cys115. Early biochemical studies established that Cys115 also covalently reacts with substrate phosphoenolpyruvate (PEP) to yield a phospholactoyl adduct, but the structural and functional consequences of this reaction remained obscure. We captured and depicted the Cys115-PEP adduct of E. cloacace MurA in various reaction states by X-ray crystallography. The data suggest that cellular MurA predominantly exists in a tightly locked complex with UDP-N-acetylmuramic acid (UNAM), the product of the MurB reaction, with PEP covalently attached to Cys115. The uniqueness and rigidity of this dormant complex was previously not recognized and presumably accounts for the failure of drug discovery efforts towards the identification of novel and effective MurA inhibitors. We demonstrate that recently published crystal structures of MurA from various organisms determined by different laboratories were indeed misinterpreted and actually contain UNAM and covalently bound PEP. The Cys115-PEP adduct was also captured in vitro during the reaction of free MurA and substrate UDP-N-acetylglucosamine (UNAG) or isomer UDP-N-acetylgalactosamine. The now available series of crystal structures allows a comprehensive view of the reaction cycle of MurA. It appears that the covalent reaction of MurA with PEP fulfills dual functions by tightening the complex with UNAM for the efficient feedback regulation of murein biosynthesis and by priming the PEP molecule for instantaneous reaction with substrate UNAG. | |||
Functional consequence of the covalent reaction of phosphoenolpyruvate with UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA).,Zhu JY, Yang Y, Han H, Betzi S, Olesen S, Marsilio F, Schonbrunn E J Biol Chem. 2012 Feb 29. PMID:22378791<ref>PMID:22378791</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3swq" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Enoylpyruvate transferase 3D structures|Enoylpyruvate transferase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | [[Category: Enterobacter cloacae subsp. cloacae ATCC 13047]] | ||
[[ | [[Category: Large Structures]] | ||
[[Category: Schonbrunn E]] | |||
== | [[Category: Yang Y]] | ||
< | [[Category: Zhu J-Y]] | ||
[[Category: Enterobacter cloacae]] | |||
[[Category: | |||
[[Category: Schonbrunn | |||
[[Category: Yang | |||
[[Category: Zhu | |||
Latest revision as of 05:25, 21 November 2024
E. Cloacae MurA in complex with Enolpyruvyl-UNAGE. Cloacae MurA in complex with Enolpyruvyl-UNAG
Structural highlights
FunctionMURA_ENTCC Cell wall formation. Adds enolpyruvyl to UDP-N-acetylglucosamine. Target for the antibiotic phosphomycin. Publication Abstract from PubMedThe enzyme MurA has been an established antibiotic target since the discovery of fosfomycin, which specifically inhibits MurA by covalent modification of the active site residue Cys115. Early biochemical studies established that Cys115 also covalently reacts with substrate phosphoenolpyruvate (PEP) to yield a phospholactoyl adduct, but the structural and functional consequences of this reaction remained obscure. We captured and depicted the Cys115-PEP adduct of E. cloacace MurA in various reaction states by X-ray crystallography. The data suggest that cellular MurA predominantly exists in a tightly locked complex with UDP-N-acetylmuramic acid (UNAM), the product of the MurB reaction, with PEP covalently attached to Cys115. The uniqueness and rigidity of this dormant complex was previously not recognized and presumably accounts for the failure of drug discovery efforts towards the identification of novel and effective MurA inhibitors. We demonstrate that recently published crystal structures of MurA from various organisms determined by different laboratories were indeed misinterpreted and actually contain UNAM and covalently bound PEP. The Cys115-PEP adduct was also captured in vitro during the reaction of free MurA and substrate UDP-N-acetylglucosamine (UNAG) or isomer UDP-N-acetylgalactosamine. The now available series of crystal structures allows a comprehensive view of the reaction cycle of MurA. It appears that the covalent reaction of MurA with PEP fulfills dual functions by tightening the complex with UNAM for the efficient feedback regulation of murein biosynthesis and by priming the PEP molecule for instantaneous reaction with substrate UNAG. Functional consequence of the covalent reaction of phosphoenolpyruvate with UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA).,Zhu JY, Yang Y, Han H, Betzi S, Olesen S, Marsilio F, Schonbrunn E J Biol Chem. 2012 Feb 29. PMID:22378791[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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