View source for 6unb


==Crystal structure of CTX-M-14 in complex with temocillin==
<StructureSection load='6unb' size='340' side='right'caption='[[6unb]], [[Resolution|resolution]] 1.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6unb]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UNB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UNB 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]] 1.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=TJ7:(2~{R},4~{S})-2-[(1~{S})-1-methoxy-2-oxidanylidene-1-[[(2~{R})-3-oxidanyl-3-oxidanylidene-2-thiophen-3-yl-propanoyl]amino]ethyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxylic+acid'>TJ7</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=6unb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6unb OCA], [https://pdbe.org/6unb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6unb RCSB], [https://www.ebi.ac.uk/pdbsum/6unb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6unb ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q9L5C7_ECOLX Q9L5C7_ECOLX] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The prevalence of multi-drug resistant Pseudomonas aeruginosa has led to the re-examination of older 'forgotten' drugs, such as temocillin, for their ability to combat resistant microbes. Temocillin is the 6-alpha-methoxy analogue of ticarcillin, a carboxypenicillin with well characterized antipseudomonal properties. The alpha-methoxy modification confers resistance to serine beta-lactamases, yet temocillin is ineffective against P. aeruginosa growth. The origins of temocillin's inferior antibacterial properties against P. aeruginosa have remained relatively unexplored. Here we analyze the reaction kinetics, protein stability, and binding conformations of temocillin and ticarcillin with penicillin-binding protein 3 (PBP3), an essential PBP in P. aeruginosa We show the 6-alpha-methoxy group perturbs the stability of the PBP3 acyl-enzyme, which manifests in an elevated koff in biochemical assays comparing temocillin with ticarcillin. Complex crystal structures with PBP3 reveal similar binding modes of the two drugs, but with important differences. Most notably, the 6-alpha-methoxy group disrupts a high-quality hydrogen bond with a conserved residue important for ligand binding, while also being inserted into a crowded active site, possibly destabilizing the active site and enabling water molecule from bulk solvent to access and cleave the acyl-enzyme bond. This hypothesis is supported by the observation that the acyl-enzyme complex of temocillin has reduced thermal stability compared with ticarcillin. Furthermore, we explore temocillin's mechanism of beta-lactamase inhibition with a high-resolution complex structure of CTX-M-14 class A serine beta-lactamase. The results suggest the alpha-methoxy group prevents hydrolysis by locking the compound into an unexpected conformation that impedes access of the catalytic water to the acyl-enzyme adduct.

Influence of the alpha-methoxy group on the reaction of temocillin with Pseudomonas aeruginosa PBP3 and CTX-M-14 beta-lactamase.,Sacco MD, Kroeck KG, Kemp MT, Zhang X, Andrews LD, Chen Y Antimicrob Agents Chemother. 2019 Nov 4. pii: AAC.01473-19. doi:, 10.1128/AAC.01473-19. PMID:31685462<ref>PMID:31685462</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6unb" style="background-color:#fffaf0;"></div>

==See Also==
*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Escherichia coli]]
[[Category: Large Structures]]
[[Category: Chen Y]]
[[Category: Sacco M]]