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==Crystal structure of the V130D mutant of OXA-24/40 in complex with doripenem== | ==Crystal structure of the V130D mutant of OXA-24/40 in complex with doripenem== | ||
<StructureSection load='3pag' size='340' side='right' caption='[[3pag]], [[Resolution|resolution]] 2.25Å' scene=''> | <StructureSection load='3pag' size='340' side='right'caption='[[3pag]], [[Resolution|resolution]] 2.25Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3pag]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3pag]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Aciba Aciba]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3PAG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3PAG FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4J6:(4R,5S)-5-[(2S,3R)-3-HYDROXY-1-OXOBUTAN-2-YL]-4-METHYL-3-({(3S,5S)-5-[(SULFAMOYLAMINO)METHYL]PYRROLIDIN-3-YL}SULFANYL)-4,5-DIHYDRO-1H-PYRROLE-2-CARBOXYLIC+ACID'>4J6</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4J6:(4R,5S)-5-[(2S,3R)-3-HYDROXY-1-OXOBUTAN-2-YL]-4-METHYL-3-({(3S,5S)-5-[(SULFAMOYLAMINO)METHYL]PYRROLIDIN-3-YL}SULFANYL)-4,5-DIHYDRO-1H-PYRROLE-2-CARBOXYLIC+ACID'>4J6</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3isg|3isg]], [[3pae|3pae]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3isg|3isg]], [[3pae|3pae]]</div></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">blaOXA-33, bla-OXA-40, blaOXA-24, blaOXA-40, oxa-24, oxa40 ([ | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">blaOXA-33, bla-OXA-40, blaOXA-24, blaOXA-40, oxa-24, oxa40 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=470 ACIBA])</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3pag FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3pag OCA], [https://pdbe.org/3pag PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3pag RCSB], [https://www.ebi.ac.uk/pdbsum/3pag PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3pag ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
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==See Also== | ==See Also== | ||
*[[Beta-lactamase|Beta-lactamase]] | *[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
| Line 28: | Line 28: | ||
[[Category: Aciba]] | [[Category: Aciba]] | ||
[[Category: Beta-lactamase]] | [[Category: Beta-lactamase]] | ||
[[Category: Large Structures]] | |||
[[Category: Leonard, D A]] | [[Category: Leonard, D A]] | ||
[[Category: Powers, R A]] | [[Category: Powers, R A]] | ||
Revision as of 11:31, 25 May 2022
Crystal structure of the V130D mutant of OXA-24/40 in complex with doripenemCrystal structure of the V130D mutant of OXA-24/40 in complex with doripenem
Structural highlights
Publication Abstract from PubMedThe emergence of class D beta-lactamases with carbapenemase activity presents an enormous challenge to health practitioners, particularly with regard to the treatment of infections caused by Gram-negative pathogens such as Acinetobacter baumanii. Unfortunately, class D beta-lactamases with carbapenemase activity are resistant to beta-lactamase inhibitors. To better understand the details of the how these enzymes bind and hydrolyze carbapenems, we have determined the structures of two deacylation-deficient variants (K84D and V130D) of the class D carbapenemase OXA-24 with doripenem bound as a covalent acyl-enzyme intermediate. Doripenem adopts essentially the same configuration in both OXA-24 variant structures, but varies significantly when compared to the non-carbapenemase class D member OXA-1/doripenem complex. The alcohol of the 6alpha hydroxyethyl moiety is directed away from the general base carboxy-K84, with implications for activation of the deacylating water. The tunnel formed by the Y112/M223 bridge in the apo form of OXA-24 is largely unchanged by the binding of doripenem. The presence of this bridge, however, causes the distal pyrrolidine/sulfonamide group to bind in a drastically different conformation compared to doripenem bound to OXA-1. The resulting difference in the position of the side-chain bridge sulfur of doripenem is consistent with the hypothesis that the tautomeric state of the pyrroline ring contributes to the different carbapenem hydrolysis rates of OXA-1 and OXA-24. These findings represent a snapshot of a key step in the catalytic mechanism of an important class D enzyme, and might be useful for the design of novel inhibitors. Structures of the Class D Carbapenemase OXA-24 from Acinetobacter baumannii in Complex with Doripenem.,Schneider KD, Ortega CJ, Renck NA, Bonomo RA, Powers RA, Leonard DA J Mol Biol. 2011 Jan 6. PMID:21215758[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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