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| | <StructureSection load='6h5o' size='340' side='right'caption='[[6h5o]], [[Resolution|resolution]] 2.82Å' scene=''> | | <StructureSection load='6h5o' size='340' side='right'caption='[[6h5o]], [[Resolution|resolution]] 2.82Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6h5o]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Staam Staam]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6H5O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6H5O FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6h5o]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus_Mu50 Staphylococcus aureus subsp. aureus Mu50]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6H5O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6H5O FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=JPP:PIPERACILLIN+(OPEN+FORM)'>JPP</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]] 2.82Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Serine-type_D-Ala-D-Ala_carboxypeptidase Serine-type D-Ala-D-Ala carboxypeptidase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.16.4 3.4.16.4] </span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=JPP:PIPERACILLIN+(OPEN+FORM)'>JPP</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=6h5o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6h5o OCA], [https://pdbe.org/6h5o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6h5o RCSB], [https://www.ebi.ac.uk/pdbsum/6h5o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6h5o 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=6h5o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6h5o OCA], [https://pdbe.org/6h5o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6h5o RCSB], [https://www.ebi.ac.uk/pdbsum/6h5o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6h5o ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/A0A0H3JPA5_STAAM A0A0H3JPA5_STAAM] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Serine-type D-Ala-D-Ala carboxypeptidase]] | + | [[Category: Staphylococcus aureus subsp. aureus Mu50]] |
| - | [[Category: Staam]]
| + | [[Category: Batuecas MT]] |
| - | [[Category: Batuecas, M T]] | + | [[Category: Hermoso JA]] |
| - | [[Category: Hermoso, J A]] | + | [[Category: Martinez-Caballero S]] |
| - | [[Category: Martinez-Caballero, S]] | + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Penicillin binding protein]]
| + | |
| Structural highlights
Function
A0A0H3JPA5_STAAM
Publication Abstract from PubMed
The quinazolinones are a new class of antibacterials with in vivo efficacy against methicillin-resistant Staphylococcus aureus (MRSA). The quinazolinones target cell wall biosynthesis and have a unique mechanism of action by binding to the allosteric site of penicillin-binding protein 2a (PBP 2a). We investigated the potential for synergism of a lead quinazolinone with several antibiotics of different classes using checkerboard and time-kill assays. The quinazolinone synergized with beta-lactam antibiotics. The combination of the quinazolinone with commercial piperacillin-tazobactam showed bactericidal synergy at sub-MICs of all three drugs. We demonstrated the efficacy of the triple-drug combination in a mouse MRSA neutropenic thigh infection model. The proposed mechanism for the synergistic activity in MRSA involves inhibition of the beta-lactamase by tazobactam, which protects piperacillin from hydrolysis, which can then inhibit its target, PBP 2. Furthermore, the quinazolinone binds to the allosteric site of PBP 2a, triggering the allosteric response. This leads to the opening of the active site, which, in turn, binds another molecule of piperacillin. In other words, PBP 2a, which is not normally inhibited by piperacillin, becomes vulnerable to inhibition in the presence of the quinazolinone. The collective effect is the impairment of cell wall biosynthesis, with bactericidal consequence. Two crystal structures for complexes of the antibiotics with PBP 2a provide support for the proposed mechanism of action.
The Quinazolinone Allosteric Inhibitor of PBP 2a Synergizes with Piperacillin and Tazobactam against Methicillin-Resistant Staphylococcus aureus.,Janardhanan J, Bouley R, Martinez-Caballero S, Peng Z, Batuecas-Mordillo M, Meisel JE, Ding D, Schroeder VA, Wolter WR, Mahasenan KV, Hermoso JA, Mobashery S, Chang M Antimicrob Agents Chemother. 2019 Apr 25;63(5). pii: AAC.02637-18. doi:, 10.1128/AAC.02637-18. Print 2019 May. PMID:30858202[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Janardhanan J, Bouley R, Martinez-Caballero S, Peng Z, Batuecas-Mordillo M, Meisel JE, Ding D, Schroeder VA, Wolter WR, Mahasenan KV, Hermoso JA, Mobashery S, Chang M. The Quinazolinone Allosteric Inhibitor of PBP 2a Synergizes with Piperacillin and Tazobactam against Methicillin-Resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2019 Apr 25;63(5). pii: AAC.02637-18. doi:, 10.1128/AAC.02637-18. Print 2019 May. PMID:30858202 doi:http://dx.doi.org/10.1128/AAC.02637-18
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