7k5v: Difference between revisions
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==OXA-48 bound by Compound 3.1== | ==OXA-48 bound by Compound 3.1== | ||
<StructureSection load='7k5v' size='340' side='right'caption='[[7k5v]]' scene=''> | <StructureSection load='7k5v' size='340' side='right'caption='[[7k5v]], [[Resolution|resolution]] 2.80Å' 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=7K5V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7K5V FirstGlance]. <br> | <table><tr><td colspan='2'>[[7k5v]] 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=7K5V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7K5V 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=7k5v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k5v OCA], [https://pdbe.org/7k5v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7k5v RCSB], [https://www.ebi.ac.uk/pdbsum/7k5v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7k5v 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]] 2.8Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BIH:NAPHTHALENE-2,6-DISULFONIC+ACID'>BIH</scene>, <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=NA:SODIUM+ION'>NA</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=7k5v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k5v OCA], [https://pdbe.org/7k5v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7k5v RCSB], [https://www.ebi.ac.uk/pdbsum/7k5v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7k5v 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 == | |||
Despite the advances in beta-lactamase inhibitor development, limited options exist for the class D carbapenemase known as OXA-48. OXA-48 is one of the most prevalent carbapenemases in carbapenem-resistant Enterobacteriaceae infections and is not susceptible to most available beta-lactamase inhibitors. Here, we screened various low-molecular-weight compounds (fragments) against OXA-48 to identify functional scaffolds for inhibitor development. Several biphenyl-, naphthalene-, fluorene-, anthraquinone-, and azobenzene-based compounds were found to inhibit OXA-48 with low micromolar potency despite their small size. Co-crystal structures of OXA-48 with several of these compounds revealed key interactions with the carboxylate-binding pocket, Arg214, and various hydrophobic residues of beta-lactamase that can be exploited in future inhibitor development. A number of the low-micromolar-potency inhibitors, across different scaffolds, synergize with ampicillin to kill Escherichia coli expressing OXA-48, albeit at high concentrations of the respective inhibitors. Additionally, several compounds demonstrated micromolar potency toward the OXA-24 and OXA-58 class D carbapenemases that are prevalent in Acinetobacter baumannii. This work provides foundational information on a variety of chemical scaffolds that can guide the design of effective OXA-48 inhibitors that maintain efficacy as well as potency toward other major class D carbapenemases. | |||
Unique Diacidic Fragments Inhibit the OXA-48 Carbapenemase and Enhance the Killing of Escherichia coli Producing OXA-48.,Taylor DM, Anglin J, Hu L, Wang L, Sankaran B, Wang J, Matzuk MM, Prasad BVV, Palzkill T ACS Infect Dis. 2021 Nov 24. doi: 10.1021/acsinfecdis.1c00501. PMID:34817169<ref>PMID:34817169</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7k5v" 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: Hu L]] | [[Category: Hu L]] | ||
Latest revision as of 18:18, 18 October 2023
OXA-48 bound by Compound 3.1OXA-48 bound by Compound 3.1
Structural highlights
FunctionPublication Abstract from PubMedDespite the advances in beta-lactamase inhibitor development, limited options exist for the class D carbapenemase known as OXA-48. OXA-48 is one of the most prevalent carbapenemases in carbapenem-resistant Enterobacteriaceae infections and is not susceptible to most available beta-lactamase inhibitors. Here, we screened various low-molecular-weight compounds (fragments) against OXA-48 to identify functional scaffolds for inhibitor development. Several biphenyl-, naphthalene-, fluorene-, anthraquinone-, and azobenzene-based compounds were found to inhibit OXA-48 with low micromolar potency despite their small size. Co-crystal structures of OXA-48 with several of these compounds revealed key interactions with the carboxylate-binding pocket, Arg214, and various hydrophobic residues of beta-lactamase that can be exploited in future inhibitor development. A number of the low-micromolar-potency inhibitors, across different scaffolds, synergize with ampicillin to kill Escherichia coli expressing OXA-48, albeit at high concentrations of the respective inhibitors. Additionally, several compounds demonstrated micromolar potency toward the OXA-24 and OXA-58 class D carbapenemases that are prevalent in Acinetobacter baumannii. This work provides foundational information on a variety of chemical scaffolds that can guide the design of effective OXA-48 inhibitors that maintain efficacy as well as potency toward other major class D carbapenemases. Unique Diacidic Fragments Inhibit the OXA-48 Carbapenemase and Enhance the Killing of Escherichia coli Producing OXA-48.,Taylor DM, Anglin J, Hu L, Wang L, Sankaran B, Wang J, Matzuk MM, Prasad BVV, Palzkill T ACS Infect Dis. 2021 Nov 24. doi: 10.1021/acsinfecdis.1c00501. PMID:34817169[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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