5cgx: Difference between revisions
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==CRYSTAL STRUCTURE OF Fox-4 cephamycinase mutant Y150F complexed with cefoxitin== | |||
<StructureSection load='5cgx' size='340' side='right'caption='[[5cgx]], [[Resolution|resolution]] 1.21Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5cgx]] is a 1 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=5CGX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CGX 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]] 1.21Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1S7:(2R)-2-{(1S)-1-METHOXY-2-OXO-1-[(THIOPHEN-2-YLACETYL)AMINO]ETHYL}-5-METHYLIDENE-5,6-DIHYDRO-2H-1,3-THIAZINE-4-CARBOXYLIC+ACID'>1S7</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=5cgx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cgx OCA], [https://pdbe.org/5cgx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5cgx RCSB], [https://www.ebi.ac.uk/pdbsum/5cgx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5cgx ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q9L387_ECOLX Q9L387_ECOLX] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Class C beta-lactamases poorly hydrolyze cephamycins (e.g., cefoxitin, cefotetan, and moxalactam). In the past 2 decades, a new family of plasmid-based AmpC beta-lactamases conferring resistance to cefoxitin, the FOX family, has grown to include nine unique members descended from the Aeromonas caviae chromosomal AmpC. To understand the basis for the unique cephamycinase activity in the FOX family, we determined the first X-ray crystal structures of FOX-4, apo enzyme and the acyl-enzyme with its namesake compound, cefoxitin, using the Y150F deacylation-deficient variant. Notably, recombinant expression of N-terminally tagged FOX-4 also yielded an inactive adenylylated enzyme form not previously observed in beta-lactamases. The posttranslational modification (PTM), which occurs on the active site Ser64, would not seem to provide a selective advantage, yet might present an opportunity for the design of novel antibacterial drugs. Substantial ligand-induced changes in the enzyme are seen in the acyl-enzyme complex, particularly the R2 loop and helix H10 (P289 to N297), with movement of F293 by 10.3 A. Taken together, this study provides the first picture of this highly proficient class C cephamycinase, uncovers a novel PTM, and suggests a possible cephamycin resistance mechanism involving repositioning of the substrate due to the presence of S153P, N289P, and N346I substitutions in the ligand binding pocket. | |||
Analysis of the Structure and Function of FOX-4 Cephamycinase.,Lefurgy ST, Malashkevich VN, Aguilan JT, Nieves E, Mundorff EC, Biju B, Noel MA, Toro R, Baiwir D, Papp-Wallace KM, Almo SC, Frere JM, Bou G, Bonomo RA Antimicrob Agents Chemother. 2015 Nov 2;60(2):717-28. doi: 10.1128/AAC.01887-15. PMID:26525784<ref>PMID:26525784</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5cgx" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==See Also== | ||
[[Category: | *[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Escherichia coli]] | |||
[[Category: Large Structures]] | |||
[[Category: Almo SC]] | |||
[[Category: Lefurgy S]] | |||
[[Category: Malashkevich VN]] | |||
[[Category: Toro R]] | |||
Latest revision as of 11:37, 27 September 2023
CRYSTAL STRUCTURE OF Fox-4 cephamycinase mutant Y150F complexed with cefoxitinCRYSTAL STRUCTURE OF Fox-4 cephamycinase mutant Y150F complexed with cefoxitin
Structural highlights
FunctionPublication Abstract from PubMedClass C beta-lactamases poorly hydrolyze cephamycins (e.g., cefoxitin, cefotetan, and moxalactam). In the past 2 decades, a new family of plasmid-based AmpC beta-lactamases conferring resistance to cefoxitin, the FOX family, has grown to include nine unique members descended from the Aeromonas caviae chromosomal AmpC. To understand the basis for the unique cephamycinase activity in the FOX family, we determined the first X-ray crystal structures of FOX-4, apo enzyme and the acyl-enzyme with its namesake compound, cefoxitin, using the Y150F deacylation-deficient variant. Notably, recombinant expression of N-terminally tagged FOX-4 also yielded an inactive adenylylated enzyme form not previously observed in beta-lactamases. The posttranslational modification (PTM), which occurs on the active site Ser64, would not seem to provide a selective advantage, yet might present an opportunity for the design of novel antibacterial drugs. Substantial ligand-induced changes in the enzyme are seen in the acyl-enzyme complex, particularly the R2 loop and helix H10 (P289 to N297), with movement of F293 by 10.3 A. Taken together, this study provides the first picture of this highly proficient class C cephamycinase, uncovers a novel PTM, and suggests a possible cephamycin resistance mechanism involving repositioning of the substrate due to the presence of S153P, N289P, and N346I substitutions in the ligand binding pocket. Analysis of the Structure and Function of FOX-4 Cephamycinase.,Lefurgy ST, Malashkevich VN, Aguilan JT, Nieves E, Mundorff EC, Biju B, Noel MA, Toro R, Baiwir D, Papp-Wallace KM, Almo SC, Frere JM, Bou G, Bonomo RA Antimicrob Agents Chemother. 2015 Nov 2;60(2):717-28. doi: 10.1128/AAC.01887-15. PMID:26525784[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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