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| | ==Avibactam and class C beta-lactamases: mechanism of inhibition, conservation of binding pocket and implications for resistance== | | ==Avibactam and class C beta-lactamases: mechanism of inhibition, conservation of binding pocket and implications for resistance== |
| - | <StructureSection load='4ooy' size='340' side='right' caption='[[4ooy]], [[Resolution|resolution]] 1.10Å' scene=''> | + | <StructureSection load='4ooy' size='340' side='right'caption='[[4ooy]], [[Resolution|resolution]] 1.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4ooy]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Pseae Pseae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OOY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OOY FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4ooy]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa_PAO1 Pseudomonas aeruginosa PAO1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OOY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OOY FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NXL:(2S,5R)-1-FORMYL-5-[(SULFOOXY)AMINO]PIPERIDINE-2-CARBOXAMIDE'>NXL</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]] 1.1Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4hef|4hef]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NXL:(2S,5R)-1-FORMYL-5-[(SULFOOXY)AMINO]PIPERIDINE-2-CARBOXAMIDE'>NXL</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ampC, PA4110 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=208964 PSEAE])</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=4ooy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ooy OCA], [https://pdbe.org/4ooy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ooy RCSB], [https://www.ebi.ac.uk/pdbsum/4ooy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ooy 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-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] </span></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=4ooy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ooy OCA], [http://pdbe.org/4ooy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ooy RCSB], [http://www.ebi.ac.uk/pdbsum/4ooy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ooy ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/AMPC_PSEAE AMPC_PSEAE] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4ooy" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4ooy" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Beta-lactamase]] | + | [[Category: Large Structures]] |
| - | [[Category: Pseae]] | + | [[Category: Pseudomonas aeruginosa PAO1]] |
| - | [[Category: Alm, R A]] | + | [[Category: Alm RA]] |
| - | [[Category: Lahiri, S D]] | + | [[Category: Lahiri SD]] |
| - | [[Category: Olivier, N B]] | + | [[Category: Olivier NB]] |
| - | [[Category: B-lactamase]]
| + | |
| - | [[Category: Carbamoylation with the inhibitor]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| Structural highlights
Function
AMPC_PSEAE
Publication Abstract from PubMed
Avibactam is a novel non-beta-lactam beta-lactamase inhibitor that inhibits a wide range of beta-lactamases. These include class A, class C and some class D enzymes, which erode the activity of beta-lactam drugs in multi-drug-resistant pathogens like Pseudomonas aeruginosa and Enterobacteriaceae. Avibactam is currently in clinical development in combination with the beta-lactam antibiotics ceftazidime, ceftaroline fosamil and aztreonam. Avibactam has the potential to be the first beta-lactamase inhibitor that could provide activity against class C-mediated resistance, which represents a growing concern in both hospital- and community-acquired infections. Avibactam has an unusual mechanism of action: it is a covalent inhibitor that acts via ring-opening but, in contrast to other currently used beta-lactamase inhibitors, this reaction is reversible. Here we present a high resolution structure of avibactam bound to a class C beta-lactamase, AmpC, from P. aeruginosa that provided insight into the mechanism of both acylation and recyclization in this enzyme class and highlighted the differences observed between class A and class C inhibition. Furthermore, variants resistant to avibactam were isolated that identified the residues that are important for inhibition. Finally, the structural information was used to predict effective inhibition by sequence analysis and functional studies of class C beta-lactamases from a large and diverse set of contemporary clinical isolates (P. aeruginosa and several Enterobacteriaceae spp.) obtained from recent infections to understand any pre-existing variability in the binding pocket that could affect inhibition by avibactam.
Avibactam and class C beta-lactamases: mechanism of inhibition, conservation of binding pocket and implications for resistance.,Lahiri SD, Johnstone M, Ross PL, McLaughlin R, Olivier NB, Alm RA Antimicrob Agents Chemother. 2014 Jul 14. pii: AAC.03057-14. PMID:25022578[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lahiri SD, Johnstone M, Ross PL, McLaughlin R, Olivier NB, Alm RA. Avibactam and class C beta-lactamases: mechanism of inhibition, conservation of binding pocket and implications for resistance. Antimicrob Agents Chemother. 2014 Jul 14. pii: AAC.03057-14. PMID:25022578 doi:http://dx.doi.org/10.1128/AAC.03057-14
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