7rpd: Difference between revisions
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==X-ray crystal structure of OXA-24/40 V130D in complex with ertapenem== | ==X-ray crystal structure of OXA-24/40 V130D in complex with ertapenem== | ||
<StructureSection load='7rpd' size='340' side='right'caption='[[7rpd]]' scene=''> | <StructureSection load='7rpd' size='340' side='right'caption='[[7rpd]], [[Resolution|resolution]] 1.95Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RPD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RPD FirstGlance]. <br> | <table><tr><td colspan='2'>[[7rpd]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RPD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RPD FirstGlance]. <br> | ||
</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=7rpd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rpd OCA], [https://pdbe.org/7rpd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rpd RCSB], [https://www.ebi.ac.uk/pdbsum/7rpd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rpd ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1RG:(4R,5S)-3-({(3S,5S)-5-[(3-CARBOXYPHENYL)CARBAMOYL]PYRROLIDIN-3-YL}SULFANYL)-5-[(1S,2R)-1-FORMYL-2-HYDROXYPROPYL]-4-METHYL-4,5-DIHYDRO-1H-PYRROLE-2-CARBOXYLIC+ACID'>1RG</scene>, <scene name='pdbligand=BCT:BICARBONATE+ION'>BCT</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
<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'>[https://proteopedia.org/fgij/fg.htm?mol=7rpd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rpd OCA], [https://pdbe.org/7rpd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rpd RCSB], [https://www.ebi.ac.uk/pdbsum/7rpd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rpd ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The evolution of multidrug resistance (MDR) in Acinetobacter spp. increases the risk of our best antibiotics losing their efficacy. From a clinical perspective, the carbapenem-hydrolyzing class D beta-lactamase (CHDL) subfamily present in Acetinobacter spp. is particularly concerning due to its ability to confer resistance to carbapenems. The kinetic profiles of class D beta-lactamases exhibit variability in carbapenem hydrolysis, suggesting functional differences. To better understand the structure-function relationship between the CHDL OXA-24/40 found in A. baumannii and carbapenem substrates, we analyzed steady-state kinetics with the carbapenem antibiotics meropenem and ertapenem, and determined the structures of complexes of OXA-24/40 bound to imipenem, meropenem, doripenem, and ertapenem, as well as the expanded-spectrum cephalosporin cefotaxime, using X-ray crystallography. We show that OXA-24/40 exhibits a preference for ertapenem compared to meropenem, imipenem, and doripenem, with an increase in catalytic efficiency of up to four-fold. We suggest that superposition of the nine OXA-24/40 complexes will better inform future inhibitor design efforts by providing insight into the complicated and varying ways in which carbapenems are selected and bound by class D beta-lactamases. | |||
Conformational flexibility in carbapenem hydrolysis drives substrate specificity of the class D carbapenemase OXA-24/40.,Mitchell JM, June CM, Baggett VL, Lowe BC, Ruble JF, Bonomo RA, Leonard DA, Powers RA J Biol Chem. 2022 Jun 13:102127. doi: 10.1016/j.jbc.2022.102127. PMID:35709986<ref>PMID:35709986</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7rpd" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Beta-lactamase]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: June | [[Category: June, C M]] | ||
[[Category: Mitchell | [[Category: Mitchell, J M]] | ||
[[Category: Powers | [[Category: Powers, R A]] | ||
[[Category: Acyl-enzyme complex]] | |||
[[Category: Carbapenemase]] | |||
[[Category: Hydrolase]] | |||
[[Category: Hydrolase-inhibitor complex]] | |||
Revision as of 21:16, 27 July 2022
X-ray crystal structure of OXA-24/40 V130D in complex with ertapenemX-ray crystal structure of OXA-24/40 V130D in complex with ertapenem
Structural highlights
Publication Abstract from PubMedThe evolution of multidrug resistance (MDR) in Acinetobacter spp. increases the risk of our best antibiotics losing their efficacy. From a clinical perspective, the carbapenem-hydrolyzing class D beta-lactamase (CHDL) subfamily present in Acetinobacter spp. is particularly concerning due to its ability to confer resistance to carbapenems. The kinetic profiles of class D beta-lactamases exhibit variability in carbapenem hydrolysis, suggesting functional differences. To better understand the structure-function relationship between the CHDL OXA-24/40 found in A. baumannii and carbapenem substrates, we analyzed steady-state kinetics with the carbapenem antibiotics meropenem and ertapenem, and determined the structures of complexes of OXA-24/40 bound to imipenem, meropenem, doripenem, and ertapenem, as well as the expanded-spectrum cephalosporin cefotaxime, using X-ray crystallography. We show that OXA-24/40 exhibits a preference for ertapenem compared to meropenem, imipenem, and doripenem, with an increase in catalytic efficiency of up to four-fold. We suggest that superposition of the nine OXA-24/40 complexes will better inform future inhibitor design efforts by providing insight into the complicated and varying ways in which carbapenems are selected and bound by class D beta-lactamases. Conformational flexibility in carbapenem hydrolysis drives substrate specificity of the class D carbapenemase OXA-24/40.,Mitchell JM, June CM, Baggett VL, Lowe BC, Ruble JF, Bonomo RA, Leonard DA, Powers RA J Biol Chem. 2022 Jun 13:102127. doi: 10.1016/j.jbc.2022.102127. PMID:35709986[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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