8v9h
From Proteopedia
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<table><tr><td colspan='2'>[[8v9h]] 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=8V9H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8V9H FirstGlance]. <br> | <table><tr><td colspan='2'>[[8v9h]] 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=8V9H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8V9H 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]] 1.5Å</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]] 1.5Å</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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=Y33:( | + | <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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=Y33:(2~{R})-2-[(2~{S},3~{R})-1,3-bis(oxidanyl)-1-oxidanylidene-butan-2-yl]-4-[(3~{S},5~{S})-5-(dimethylcarbamoyl)pyrrolidin-3-yl]sulfanyl-2-methyl-1,3-dihydropyrrole-5-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=8v9h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8v9h OCA], [https://pdbe.org/8v9h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8v9h RCSB], [https://www.ebi.ac.uk/pdbsum/8v9h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8v9h ProSAT]</span></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=8v9h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8v9h OCA], [https://pdbe.org/8v9h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8v9h RCSB], [https://www.ebi.ac.uk/pdbsum/8v9h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8v9h ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| - | == | + | <div style="background-color:#fffaf0;"> |
| - | + | == Publication Abstract from PubMed == | |
| + | Carbapenem antibiotics are used as a last-resort treatment for infections caused by multidrug-resistant bacteria. The wide spread of carbapenemases in Gram-negative bacteria has severely compromised the utility of these drugs and represents a serious public health threat. To combat carbapenemase-mediated resistance, new antimicrobials and inhibitors of these enzymes are urgently needed. Here, we describe the interaction of the atypically C5alpha-methyl-substituted carbapenem, NA-1-157, with the GES-5 carbapenemase. MICs of this compound against Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii producing the enzyme were reduced 4-16-fold when compared to MICs of the commercial carbapenems, reaching clinically sensitive breakpoints. When NA-1-157 was combined with meropenem, a strong synergistic effect was observed. Kinetic and ESI-LC/MS studies demonstrated that NA-1-157 is a potent inhibitor of GES-5, with a high inactivation efficiency of (2.9 +/- 0.9) x 10(5) M(-1) s(-1). Acylation of GES-5 by NA-1-157 was biphasic, with the fast phase completing within seconds, and the slow phase taking several hours and likely proceeding through a reversible tetrahedral intermediate. Deacylation was extremely slow (k(3) = (2.4 +/- 0.3) x 10(-7) s(-1)), resulting in a residence time of 48 +/- 6 days. MD simulation of the GES-5-meropenem and GES-5-NA-1-157 acyl-enzyme complexes revealed that the C5alpha-methyl group in NA-1-157 sterically restricts rotation of the 6alpha-hydroxyethyl group preventing ingress of the deacylating water into the vicinity of the scissile bond of the acyl-enzyme intermediate. These data demonstrate that NA-1-157 is a potent irreversible inhibitor of the GES-5 carbapenemase. | ||
| + | |||
| + | Restricted Rotational Flexibility of the C5alpha-Methyl-Substituted Carbapenem NA-1-157 Leads to Potent Inhibition of the GES-5 Carbapenemase.,Stewart NK, Toth M, Quan P, Beer M, Buynak JD, Smith CA, Vakulenko SB ACS Infect Dis. 2024 Apr 12;10(4):1232-1249. doi: 10.1021/acsinfecdis.3c00683. , Epub 2024 Mar 21. PMID:38511828<ref>PMID:38511828</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 8v9h" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Current revision
GES-5-NA-1-157 complex
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