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| | ==Crystal structure of unbound OXA-48== | | ==Crystal structure of unbound OXA-48== |
| - | <StructureSection load='4s2p' size='340' side='right' caption='[[4s2p]], [[Resolution|resolution]] 1.70Å' scene=''> | + | <StructureSection load='4s2p' size='340' side='right'caption='[[4s2p]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4s2p]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_pneumoniae"_(schroeter_1886)_flugge_1886 "bacillus pneumoniae" (schroeter 1886) flugge 1886]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4S2P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4S2P FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4s2p]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Klebsiella_pneumoniae Klebsiella pneumoniae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4S2P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4S2P FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=KCX:LYSINE+NZ-CARBOXYLIC+ACID'>KCX</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">[[3hbr|3hbr]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=KCX:LYSINE+NZ-CARBOXYLIC+ACID'>KCX</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">bla OXA-48, blaOXA-48, FP68_27275, KPE71T_00045 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=573 "Bacillus pneumoniae" (Schroeter 1886) Flugge 1886])</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=4s2p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4s2p OCA], [https://pdbe.org/4s2p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4s2p RCSB], [https://www.ebi.ac.uk/pdbsum/4s2p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4s2p 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=4s2p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4s2p OCA], [http://pdbe.org/4s2p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4s2p RCSB], [http://www.ebi.ac.uk/pdbsum/4s2p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4s2p ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/BLO48_KLEPN BLO48_KLEPN] Class D beta-lactamase which confers resistance to the beta-lactam antibiotics, including amoxicillin, and moderate resistance to cephalosporins and carbapenems such as cephalothin and imipenem; in the DH10B strain of E.coli (PubMed:14693513). Acts via hydrolysis of the beta-lactam ring (PubMed:14693513, PubMed:19477418, PubMed:27073009, PubMed:38161376). Has oxacillin-, cephalothin- and imipenem-hydrolyzing activities (PubMed:14693513, PubMed:19477418, PubMed:27073009, PubMed:38161376).<ref>PMID:14693513</ref> <ref>PMID:19477418</ref> <ref>PMID:27073009</ref> <ref>PMID:38161376</ref> |
| | <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 4s2p" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4s2p" 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: Klebsiella pneumoniae]] |
| - | [[Category: King, D T]] | + | [[Category: Large Structures]] |
| - | [[Category: Strynadka, N C.J]] | + | [[Category: King DT]] |
| - | [[Category: Hydrolase]] | + | [[Category: Strynadka NCJ]] |
| Structural highlights
Function
BLO48_KLEPN Class D beta-lactamase which confers resistance to the beta-lactam antibiotics, including amoxicillin, and moderate resistance to cephalosporins and carbapenems such as cephalothin and imipenem; in the DH10B strain of E.coli (PubMed:14693513). Acts via hydrolysis of the beta-lactam ring (PubMed:14693513, PubMed:19477418, PubMed:27073009, PubMed:38161376). Has oxacillin-, cephalothin- and imipenem-hydrolyzing activities (PubMed:14693513, PubMed:19477418, PubMed:27073009, PubMed:38161376).[1] [2] [3] [4]
Publication Abstract from PubMed
Emerging beta-lactamase-mediated resistance is threatening the clinical utility of the single most prominent class of antibacterial agents used in medicine, the beta-lactams. The diazabicyclooctane avibactam is able to inhibit a wider range of serine beta-lactamases than has been previously observed with beta-lactamase inhibitors such as the widely prescribed clavulanic acid. However, despite its broad-spectrum activity, variable levels of inhibition have been observed for molecular class D beta-lactamases. In order to better understand the molecular basis and spectrum of inhibition by avibactam, we provide structural and mechanistic analysis of the compound in complex with important class A and D serine beta-lactamases. Herein, we reveal the 1.7- and 2.0-A-resolution crystal structures of avibactam covalently bound to class D beta-lactamases OXA-10 and OXA-48. Furthermore, a kinetic analysis of key active-site mutants for class A beta-lactamase CTX-M-15 allows us to propose a validated mechanism for avibactam-mediated beta-lactamase inhibition including a unique role for S130, which acts as a general base. This study provides molecular insights that will aid in the design and development of avibactam-based chemotherapeutic agents effective against emerging drug-resistant microorganisms.
Molecular Mechanism of Avibactam-Mediated beta-Lactamase Inhibition.,King DT, King AM, Lal SM, Wright GD, Strynadka NC ACS Infect Dis. 2015 Apr 10;1(4):175-84. doi: 10.1021/acsinfecdis.5b00007. Epub, 2015 Feb 11. PMID:27622530[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Poirel L, Héritier C, Tolün V, Nordmann P. Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae. Antimicrob Agents Chemother. 2004 Jan;48(1):15-22. PMID:14693513 doi:10.1128/AAC.48.1.15-22.2004
- ↑ Docquier JD, Calderone V, De Luca F, Benvenuti M, Giuliani F, Bellucci L, Tafi A, Nordmann P, Botta M, Rossolini GM, Mangani S. Crystal structure of the OXA-48 beta-lactamase reveals mechanistic diversity among class D carbapenemases. Chem Biol. 2009 May 29;16(5):540-7. PMID:19477418 doi:10.1016/j.chembiol.2009.04.010
- ↑ Stojanoski V, Adamski CJ, Hu L, Mehta SC, Sankaran B, Zwart P, Prasad BV, Palzkill T. Removal of the Side Chain at the Active-Site Serine by a Glycine Substitution Increases the Stability of a Wide Range of Serine beta-Lactamases by Relieving Steric Strain. Biochemistry. 2016 May 3;55(17):2479-90. doi: 10.1021/acs.biochem.6b00056. Epub, 2016 Apr 22. PMID:27073009 doi:http://dx.doi.org/10.1021/acs.biochem.6b00056
- ↑ Zhou Q, Catalán P, Bell H, Baumann P, Cooke R, Evans R, Yang J, Zhang Z, Zappalà D, Zhang Y, Blackburn GM, He Y, Jin Y. An Ion-Pair Induced Intermediate Complex Captured in Class D Carbapenemase Reveals Chloride Ion as a Janus Effector Modulating Activity. ACS Cent Sci. 2023 Dec 13;9(12):2339-2349. PMID:38161376 doi:10.1021/acscentsci.3c00609
- ↑ King DT, King AM, Lal SM, Wright GD, Strynadka NC. Molecular Mechanism of Avibactam-Mediated beta-Lactamase Inhibition. ACS Infect Dis. 2015 Apr 10;1(4):175-84. doi: 10.1021/acsinfecdis.5b00007. Epub, 2015 Feb 11. PMID:27622530 doi:http://dx.doi.org/10.1021/acsinfecdis.5b00007
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