View source for 8faj


==OXA-48-NA-1-157 inhibitor complex==
<StructureSection load='8faj' size='340' side='right'caption='[[8faj]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8faj]] 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=8FAJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FAJ 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]] 1.75&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=Y33:(5R)-5-[(1S,2R)-1-carboxy-2-hydroxypropyl]-3-{[(3S,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]sulfanyl}-5-methyl-4,5-dihydro-1H-pyrrole-2-carboxylic+acid'>Y33</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=8faj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8faj OCA], [https://pdbe.org/8faj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8faj RCSB], [https://www.ebi.ac.uk/pdbsum/8faj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8faj ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q6XEC0_KLEPN Q6XEC0_KLEPN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The wide spread of carbapenem-hydrolyzing beta-lactamases in Gram-negative bacteria has diminished the utility of the last-resort carbapenem antibiotics, significantly narrowing the available therapeutic options. In the Enterobacteriaceae family, which includes many important clinical pathogens such as Klebsiella pneumoniae and Escherichia coli, production of class D beta-lactamases from the OXA-48-type family constitutes the major mechanism of resistance to carbapenems. To address the public health threat posed by these enzymes, novel, effective therapeutics are urgently needed. Here, we report evaluation of a novel, C5alpha-methyl-substituted carbapenem, NA-1-157, and show that its MICs against bacteria producing OXA-48-type enzymes were reduced by 4- to 32-fold when compared to meropenem. When combined with commercial carbapenems, the potency of NA-1-157 was further enhanced, resulting in target potentiation concentrations ranging from 0.125 to 2 mug/mL. Kinetic studies demonstrated that the compound is poorly hydrolyzed by OXA-48, with a catalytic efficiency 30- to 50-fold lower than those of imipenem and meropenem. Acylation of OXA-48 by NA-1-157 was severely impaired, with a rate 10,000- to 36,000-fold slower when compared to the commercial carbapenems. Docking, molecular dynamics, and structural studies demonstrated that the presence of the C5alpha-methyl group in NA-1-157 creates steric clashes within the active site, leading to differences in the position and the hydrogen-bonding pattern of the compound, which are incompatible with efficient acylation. This study demonstrates that NA-1-157 is a promising novel carbapenem for treatment of infections caused by OXA-48-producing bacterial pathogens.

The C5alpha-Methyl-Substituted Carbapenem NA-1-157 Exhibits Potent Activity against Klebsiella spp. Isolates Producing OXA-48-Type Carbapenemases.,Smith CA, Stewart NK, Toth M, Quan P, Buynak JD, Vakulenko SB ACS Infect Dis. 2023 May 12;9(5):1123-1136. doi: 10.1021/acsinfecdis.3c00059. , Epub 2023 May 2. PMID:37130087<ref>PMID:37130087</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8faj" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Klebsiella pneumoniae]]
[[Category: Large Structures]]
[[Category: Smith CA]]
[[Category: Stewart NK]]
[[Category: Toth M]]
[[Category: Vakulenko SB]]