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| | <StructureSection load='5fgz' size='340' side='right'caption='[[5fgz]], [[Resolution|resolution]] 2.85Å' scene=''> | | <StructureSection load='5fgz' size='340' side='right'caption='[[5fgz]], [[Resolution|resolution]] 2.85Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5fgz]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Ecoli Ecoli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FGZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5FGZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5fgz]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FGZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5FGZ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5VW:[[(3~{R},6~{S})-1-METHANOYL-6-[[(3~{S})-PYRROLIDIN-3-YL]OXYCARBAMOYL]PIPERIDIN-3-YL]AMINO]+HYDROGEN+SULFATE'>5VW</scene>, <scene name='pdbligand=M0E:MOENOMYCIN'>M0E</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]] 2.85Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">mrcB, pbpF, ponB, b0149, JW0145 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83333 ECOLI])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5VW:[[(3~{R},6~{S})-1-METHANOYL-6-[[(3~{S})-PYRROLIDIN-3-YL]OXYCARBAMOYL]PIPERIDIN-3-YL]AMINO]+HYDROGEN+SULFATE'>5VW</scene>, <scene name='pdbligand=M0E:MOENOMYCIN'>M0E</scene></td></tr> |
| - | <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=5fgz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fgz OCA], [http://pdbe.org/5fgz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fgz RCSB], [http://www.ebi.ac.uk/pdbsum/5fgz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5fgz ProSAT]</span></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=5fgz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fgz OCA], [https://pdbe.org/5fgz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5fgz RCSB], [https://www.ebi.ac.uk/pdbsum/5fgz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5fgz ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PBPB_ECOLI PBPB_ECOLI]] Cell wall formation. Synthesis of cross-linked peptidoglycan from the lipid intermediates. The enzyme has a penicillin-insensitive transglycosylase N-terminal domain (formation of linear glycan strands) and a penicillin-sensitive transpeptidase C-terminal domain (cross-linking of the peptide subunits). | + | [https://www.uniprot.org/uniprot/PBPB_ECOLI PBPB_ECOLI] Cell wall formation. Synthesis of cross-linked peptidoglycan from the lipid intermediates. The enzyme has a penicillin-insensitive transglycosylase N-terminal domain (formation of linear glycan strands) and a penicillin-sensitive transpeptidase C-terminal domain (cross-linking of the peptide subunits). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Ecoli]] | + | [[Category: Escherichia coli K-12]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: King, D T]] | + | [[Category: King DT]] |
| - | [[Category: Strynadka, N C.J]] | + | [[Category: Strynadka NCJ]] |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Penicillin-binding-protein]]
| + | |
| Structural highlights
Function
PBPB_ECOLI Cell wall formation. Synthesis of cross-linked peptidoglycan from the lipid intermediates. The enzyme has a penicillin-insensitive transglycosylase N-terminal domain (formation of linear glycan strands) and a penicillin-sensitive transpeptidase C-terminal domain (cross-linking of the peptide subunits).
Publication Abstract from PubMed
Avibactam is a diazabicyclooctane beta-lactamase inhibitor possessing outstanding but incomplete efficacy against multidrug-resistant Gram-negative pathogens in combination with beta-lactam antibiotics. Significant pharmaceutical investment in generating derivatives of avibactam warrants a thorough characterization of their activity. We show here through structural and kinetic analysis that select diazabicyclooctane derivatives display effective but varied inhibition of two clinically important beta-lactamases (CTX-M-15 and OXA-48). Furthermore, these derivatives exhibit considerable antimicrobial activity (MIC </= 2 mug/mL) against clinical isolates of Pseudomonas aeruginosa, Escherichia coli, and Enterobacter spp. Imaging of cell phenotype along with structural and biochemical experiments unambiguously demonstrate that this activity, in E. coli, is a result of targeting penicillin-binding protein 2. Our results suggest that structure-activity relationship studies for the purpose of drug discovery must consider both beta-lactamases and penicillin-binding proteins as targets. We believe that this approach will yield next-generation combination or monotherapies with an expanded spectrum of activity against currently untreatable Gram-negative pathogens.
Structural and Kinetic Characterization of Diazabicyclooctanes as Dual Inhibitors of Both Serine-beta-Lactamases and Penicillin-Binding Proteins.,King AM, King DT, French S, Brouillette E, Asli A, Alexander JA, Vuckovic M, Maiti SN, Parr TR Jr, Brown ED, Malouin F, Strynadka NC, Wright GD ACS Chem Biol. 2016 Jan 14. PMID:26731698[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ King AM, King DT, French S, Brouillette E, Asli A, Alexander JA, Vuckovic M, Maiti SN, Parr TR Jr, Brown ED, Malouin F, Strynadka NC, Wright GD. Structural and Kinetic Characterization of Diazabicyclooctanes as Dual Inhibitors of Both Serine-beta-Lactamases and Penicillin-Binding Proteins. ACS Chem Biol. 2016 Jan 14. PMID:26731698 doi:http://dx.doi.org/10.1021/acschembio.5b00944
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