7aw5: Difference between revisions
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==Crystal structure of OXA-48 beta-lactamase in the complex with the inhibitor ID3== | ==Crystal structure of OXA-48 beta-lactamase in the complex with the inhibitor ID3== | ||
<StructureSection load='7aw5' size='340' side='right'caption='[[7aw5]]' scene=''> | <StructureSection load='7aw5' size='340' side='right'caption='[[7aw5]], [[Resolution|resolution]] 1.65Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AW5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AW5 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7aw5]] 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=7AW5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AW5 FirstGlance]. <br> | ||
</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=7aw5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7aw5 OCA], [https://pdbe.org/7aw5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7aw5 RCSB], [https://www.ebi.ac.uk/pdbsum/7aw5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7aw5 ProSAT]</span></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]] 1.65Å</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=KCX:LYSINE+NZ-CARBOXYLIC+ACID'>KCX</scene>, <scene name='pdbligand=LKH:4-[(~{E})-[3-(4-chlorophenyl)-5-sulfanylidene-1~{H}-1,2,4-triazol-4-yl]iminomethyl]benzoic+acid'>LKH</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=7aw5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7aw5 OCA], [https://pdbe.org/7aw5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7aw5 RCSB], [https://www.ebi.ac.uk/pdbsum/7aw5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7aw5 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/Q6XEC0_KLEPN Q6XEC0_KLEPN] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The major cause of bacterial resistance to beta-lactams is the production of hydrolytic beta-lactamase enzymes. Nowadays, the combination of beta-lactam antibiotics with beta-lactamase inhibitors (BLIs) is the main strategy for overcoming such issues. Nevertheless, particularly challenging beta-lactamases, such as OXA-48, pose the need for novel and effective treatments. Herein, we describe the screening of a proprietary compound collection against Klebsiella pneumoniae OXA-48, leading to the identification of several chemotypes, like the 4-ideneamino-4H-1,2,4-triazole (SC_2) and pyrazolo[3,4-b]pyridine (SC_7) cores as potential inhibitors. Importantly, the most potent representative of the latter series (ID2, AC50 = 0.99 muM) inhibited OXA-48 via a reversible and competitive mechanism of action, as demonstrated by biochemical and X-ray studies; furthermore, it slightly improved imipenem's activity in Escherichia coli ATCC BAA-2523 beta-lactam resistant strain. Also, ID2 showed good solubility and no sign of toxicity up to the highest tested concentration, resulting in a promising starting point for further optimization programs toward novel and effective non-beta-lactam BLIs. | |||
Discovery of Novel Chemical Series of OXA-48 beta-Lactamase Inhibitors by High-Throughput Screening.,Garofalo B, Prati F, Buonfiglio R, Coletta I, D'Atanasio N, Molteni A, Carettoni D, Wanke V, Pochetti G, Montanari R, Capelli D, Milanese C, Di Giorgio FP, Ombrato R Pharmaceuticals (Basel). 2021 Jun 25;14(7). pii: ph14070612. doi:, 10.3390/ph14070612. PMID:34202402<ref>PMID:34202402</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7aw5" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Klebsiella pneumoniae]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Capelli D]] | [[Category: Capelli D]] | ||