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| | ==Vibrio cholerae family 3 glycoside hydrolase (NagZ) in complex with PUGNAc== | | ==Vibrio cholerae family 3 glycoside hydrolase (NagZ) in complex with PUGNAc== |
| - | <StructureSection load='2oxn' size='340' side='right' caption='[[2oxn]], [[Resolution|resolution]] 1.70Å' scene=''> | + | <StructureSection load='2oxn' size='340' side='right'caption='[[2oxn]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2oxn]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillo_virgola_del_koch"_trevisan_1884 "bacillo virgola del koch" trevisan 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OXN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2OXN FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2oxn]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Vibrio_cholerae Vibrio cholerae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OXN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2OXN FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=OAN:O-(2-ACETAMIDO-2-DEOXY+D-GLUCOPYRANOSYLIDENE)+AMINO-N-PHENYLCARBAMATE'>OAN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1tr9|1tr9]], [[1y65|1y65]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OAN:O-(2-ACETAMIDO-2-DEOXY+D-GLUCOPYRANOSYLIDENE)+AMINO-N-PHENYLCARBAMATE'>OAN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">nagZ ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=666 "Bacillo virgola del Koch" Trevisan 1884])</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=2oxn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2oxn OCA], [https://pdbe.org/2oxn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2oxn RCSB], [https://www.ebi.ac.uk/pdbsum/2oxn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2oxn ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Beta-N-acetylhexosaminidase Beta-N-acetylhexosaminidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.52 3.2.1.52] </span></td></tr>
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| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2oxn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2oxn OCA], [http://pdbe.org/2oxn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2oxn RCSB], [http://www.ebi.ac.uk/pdbsum/2oxn PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/NAGZ_VIBCH NAGZ_VIBCH]] Plays a role in peptidoglycan recycling by cleaving the terminal beta-1,4-linked N-acetylglucosamine (GlcNAc) from peptide-linked peptidoglycan fragments, giving rise to free GlcNAc, anhydro-N-acetylmuramic acid and anhydro-N-acetylmuramic acid-linked peptides. Plays a role in beta-lactam antibiotic resistance via its role in generating anhydro-N-acetylmuramic acid-linked peptides; these peptides function as signaling molecules that induce high-level expression of the beta-lactamase AmpC.<ref>PMID:24009110</ref> <ref>PMID:17439950</ref> <ref>PMID:19499593</ref> | + | [https://www.uniprot.org/uniprot/NAGZ_VIBCH NAGZ_VIBCH] Plays a role in peptidoglycan recycling by cleaving the terminal beta-1,4-linked N-acetylglucosamine (GlcNAc) from peptide-linked peptidoglycan fragments, giving rise to free GlcNAc, anhydro-N-acetylmuramic acid and anhydro-N-acetylmuramic acid-linked peptides. Plays a role in beta-lactam antibiotic resistance via its role in generating anhydro-N-acetylmuramic acid-linked peptides; these peptides function as signaling molecules that induce high-level expression of the beta-lactamase AmpC.<ref>PMID:24009110</ref> <ref>PMID:17439950</ref> <ref>PMID:19499593</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ox/2oxn_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ox/2oxn_consurf.spt"</scriptWhenChecked> |
| | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
| - | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2oxn ConSurf]. |
| | <div style="clear:both"></div> | | <div style="clear:both"></div> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
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| | ==See Also== | | ==See Also== |
| | *[[Beta-Hexosaminidase|Beta-Hexosaminidase]] | | *[[Beta-Hexosaminidase|Beta-Hexosaminidase]] |
| - | *[[Matrix metalloproteinase|Matrix metalloproteinase]] | + | *[[Beta-Hexosaminidase 3D structures|Beta-Hexosaminidase 3D structures]] |
| | + | *[[Beta-N-acetylhexosaminidase 3D structures|Beta-N-acetylhexosaminidase 3D structures]] |
| | + | *[[Matrix metalloproteinase 3D structures|Matrix metalloproteinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Bacillo virgola del koch trevisan 1884]] | + | [[Category: Large Structures]] |
| - | [[Category: Beta-N-acetylhexosaminidase]] | + | [[Category: Vibrio cholerae]] |
| - | [[Category: Balcewich, M]] | + | [[Category: Balcewich M]] |
| - | [[Category: Mark, B L]] | + | [[Category: Mark BL]] |
| - | [[Category: Hydrolase]]
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| - | [[Category: Tim-barrel]]
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| Structural highlights
Function
NAGZ_VIBCH Plays a role in peptidoglycan recycling by cleaving the terminal beta-1,4-linked N-acetylglucosamine (GlcNAc) from peptide-linked peptidoglycan fragments, giving rise to free GlcNAc, anhydro-N-acetylmuramic acid and anhydro-N-acetylmuramic acid-linked peptides. Plays a role in beta-lactam antibiotic resistance via its role in generating anhydro-N-acetylmuramic acid-linked peptides; these peptides function as signaling molecules that induce high-level expression of the beta-lactamase AmpC.[1] [2] [3]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The increasing spread of plasmid-borne ampC-ampR operons is of considerable medical importance, since the AmpC beta-lactamases they encode confer high level resistance to many third generation cephalosporins. Induction of AmpC beta-lactamase from endogenous or plasmid-borne ampC-ampR operons is mediated by a catabolic inducer molecule, 1,6-anhydro-N-acetylmuramic acid (MurNAc) tripeptide, an intermediate of the cell wall recycling pathway derived from the peptidoglycan. Here we describe a strategy for attenuating the antibiotic resistance associated with the ampC-ampR operon by blocking the formation of the inducer molecule using small molecule inhibitors of NagZ, the glycoside hydrolase catalyzing the formation of this inducer molecule. The structure of the NagZ-inhibitor complex provides insight into the molecular basis for inhibition and enables the development of inhibitors with 100-fold selectivity for NagZ over functionally related human enzymes. These PUGNAc-derived inhibitors reduce the minimal inhibitory concentration (MIC) values for several clinically relevant cephalosporins in both wild-type and AmpC-hyperproducing strains lacking functional AmpD.
Small molecule inhibitors of a glycoside hydrolase attenuate inducible AmpC-mediated beta-lactam resistance.,Stubbs KA, Balcewich M, Mark BL, Vocadlo DJ J Biol Chem. 2007 Jul 20;282(29):21382-91. Epub 2007 Apr 16. PMID:17439950[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Stubbs KA, Bacik JP, Perley-Robertson GE, Whitworth GE, Gloster TM, Vocadlo DJ, Mark BL. The Development of Selective Inhibitors of NagZ: Increased Susceptibility of Gram-Negative Bacteria to beta-Lactams. Chembiochem. 2013 Oct 11;14(15):1973-81. doi: 10.1002/cbic.201300395. Epub 2013, Sep 5. PMID:24009110 doi:http://dx.doi.org/10.1002/cbic.201300395
- ↑ Stubbs KA, Balcewich M, Mark BL, Vocadlo DJ. Small molecule inhibitors of a glycoside hydrolase attenuate inducible AmpC-mediated beta-lactam resistance. J Biol Chem. 2007 Jul 20;282(29):21382-91. Epub 2007 Apr 16. PMID:17439950 doi:10.1074/jbc.M700084200
- ↑ Balcewich MD, Stubbs KA, He Y, James TW, Davies GJ, Vocadlo DJ, Mark BL. Insight into a strategy for attenuating AmpC-mediated beta-lactam resistance: Structural basis for selective inhibition of the glycoside hydrolase NagZ. Protein Sci. 2009 Apr 16. PMID:19499593 doi:10.1002/pro.137
- ↑ Stubbs KA, Balcewich M, Mark BL, Vocadlo DJ. Small molecule inhibitors of a glycoside hydrolase attenuate inducible AmpC-mediated beta-lactam resistance. J Biol Chem. 2007 Jul 20;282(29):21382-91. Epub 2007 Apr 16. PMID:17439950 doi:10.1074/jbc.M700084200
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