View source for 5qag


==OXA-48 IN COMPLEX WITH COMPOUND 9a==
<StructureSection load='5qag' size='340' side='right'caption='[[5qag]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5qag]] is a 4 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=5QAG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5QAG FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=KCX:LYSINE+NZ-CARBOXYLIC+ACID'>KCX</scene>, <scene name='pdbligand=Q2R:3-(2-methoxycarbonylphenyl)benzoic+acid'>Q2R</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=5qag FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5qag OCA], [https://pdbe.org/5qag PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5qag RCSB], [https://www.ebi.ac.uk/pdbsum/5qag PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5qag ProSAT]</span></td></tr>
</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;">
== Publication Abstract from PubMed ==
beta-Lactam antibiotics are of utmost importance when treating bacterial infections in the medical community. However, currently their utility is threatened by the emergence and spread of beta-lactam resistance. The most prevalent resistance mechanism to beta-lactam antibiotics is expression of beta-lactamase enzymes. One way to overcome resistance caused by beta-lactamases, is the development of beta-lactamase inhibitors and today several beta-lactamase inhibitors e.g. avibactam, are approved in the clinic. Our focus is the oxacillinase-48 (OXA-48), an enzyme reported to spread rapidly across the world and commonly identified in Escherichia coli and Klebsiella pneumoniae. To guide inhibitor design, we used diversely substituted 3-aryl and 3-heteroaryl benzoic acids to probe the active site of OXA-48 for useful enzyme-inhibitor interactions. In the presented study, a focused fragment library containing 49 3-substituted benzoic acid derivatives were synthesised and biochemically characterized. Based on crystallographic data from 33 fragment-enzyme complexes, the fragments could be classified into R(1) or R(2) binders by their overall binding conformation in relation to the binding of the R(1) and R(2) side groups of imipenem. Moreover, binding interactions attractive for future inhibitor design were found and their usefulness explored by the rational design and evaluation of merged inhibitors from orthogonally binding fragments. The best inhibitors among the resulting 3,5-disubstituted benzoic acids showed inhibitory potential in the low micromolar range (IC50=2.9muM). For these inhibitors, the complex X-ray structures revealed non-covalent binding to Arg250, Arg214 and Tyr211 in the active site and the interactions observed with the mono-substituted fragments were also identified in the merged structures.

A focused fragment library targeting the antibiotic resistance enzyme - Oxacillinase-48: Synthesis, structural evaluation and inhibitor design.,Akhter S, Lund BA, Ismael A, Langer M, Isaksson J, Christopeit T, Leiros HS, Bayer A Eur J Med Chem. 2018 Feb 10;145:634-648. doi: 10.1016/j.ejmech.2017.12.085. Epub , 2017 Dec 30. PMID:29348071<ref>PMID:29348071</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5qag" style="background-color:#fffaf0;"></div>

==See Also==
*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Klebsiella pneumoniae]]
[[Category: Large Structures]]
[[Category: Leiros HKS]]
[[Category: Lund BA]]