5wi3: Difference between revisions
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==Structure of Acinetobacter baumannii carbapenemase OXA-239 K82D bound to cefotaxime== | |||
<StructureSection load='5wi3' size='340' side='right'caption='[[5wi3]], [[Resolution|resolution]] 1.81Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5wi3]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Acinetobacter_sp._enrichment_culture_clone_8407 Acinetobacter sp. enrichment culture clone 8407]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WI3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5WI3 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]] 1.81Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CEF:CEFOTAXIME,+C3+CLEAVED,+OPEN,+BOUND+FORM'>CEF</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=5wi3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wi3 OCA], [https://pdbe.org/5wi3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5wi3 RCSB], [https://www.ebi.ac.uk/pdbsum/5wi3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5wi3 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/I6YCI1_9GAMM I6YCI1_9GAMM] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
OXA-239 is a class D carbapenemase isolated from an Acinetobacter baumannii strain found in Mexico. This enzyme is a variant of OXA-23 with three amino acid substitutions in or near the active site. These substitutions cause OXA-239 to hydrolyze late-generation cephalosporins and the monobactam aztreonam with greater efficiency than OXA-23. OXA-239 activity against the carbapenems doripenem and imipenem is reduced approximately 3-fold and 20-fold respectively. Further analysis demonstrated that two of the substitutions (P225S and D222N) are largely responsible for the observed alteration of kinetic parameters, while the third (S109L) may serve to stabilize the protein. Structures of OXA-239 with cefotaxime, doripenem and imipenem bound as acyl-intermediates were determined. These structures reveal that OXA-239 has increased flexibility in a loop that contains P225S and D222N. When carbapenems are bound, the conformation of this loop is essentially identical to that observed previously for OXA-23, with a narrow active site that makes extensive contacts to the ligand. When cefotaxime is bound, the loop can adopt a different conformation that widens the active site to allow binding of that bulky drug. This alternate conformation is made possible by P225S and further stabilized by D222N. Taken together, these results suggest that the three substitutions were selected to expand the substrate specificity profile of OXA-23 to cephalosporins and monobactams. The loss of activity against imipenem, however, suggests that there may be limits to the plasticity of class D enzymes with regard to evolving active sites that can effectively bind multiple classes of beta-lactam drugs. | |||
Multiple substitutions lead to increased loop flexibility and expanded specificity in Acinetobacter baumannii carbapenemase OXA-239.,Harper TM, June CM, Taracila MA, Bonomo RA, Powers RA, Leonard DA Biochem J. 2017 Dec 11. pii: BCJ20170702. doi: 10.1042/BCJ20170702. PMID:29229762<ref>PMID:29229762</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Harper | <div class="pdbe-citations 5wi3" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
</StructureSection> | |||
[[Category: Acinetobacter sp. enrichment culture clone 8407]] | |||
[[Category: Large Structures]] | |||
[[Category: Harper TM]] | |||
[[Category: June CM]] | |||
[[Category: Leonard DA]] | |||
[[Category: Powers RA]] | |||
Latest revision as of 17:13, 4 October 2023
Structure of Acinetobacter baumannii carbapenemase OXA-239 K82D bound to cefotaximeStructure of Acinetobacter baumannii carbapenemase OXA-239 K82D bound to cefotaxime
Structural highlights
FunctionPublication Abstract from PubMedOXA-239 is a class D carbapenemase isolated from an Acinetobacter baumannii strain found in Mexico. This enzyme is a variant of OXA-23 with three amino acid substitutions in or near the active site. These substitutions cause OXA-239 to hydrolyze late-generation cephalosporins and the monobactam aztreonam with greater efficiency than OXA-23. OXA-239 activity against the carbapenems doripenem and imipenem is reduced approximately 3-fold and 20-fold respectively. Further analysis demonstrated that two of the substitutions (P225S and D222N) are largely responsible for the observed alteration of kinetic parameters, while the third (S109L) may serve to stabilize the protein. Structures of OXA-239 with cefotaxime, doripenem and imipenem bound as acyl-intermediates were determined. These structures reveal that OXA-239 has increased flexibility in a loop that contains P225S and D222N. When carbapenems are bound, the conformation of this loop is essentially identical to that observed previously for OXA-23, with a narrow active site that makes extensive contacts to the ligand. When cefotaxime is bound, the loop can adopt a different conformation that widens the active site to allow binding of that bulky drug. This alternate conformation is made possible by P225S and further stabilized by D222N. Taken together, these results suggest that the three substitutions were selected to expand the substrate specificity profile of OXA-23 to cephalosporins and monobactams. The loss of activity against imipenem, however, suggests that there may be limits to the plasticity of class D enzymes with regard to evolving active sites that can effectively bind multiple classes of beta-lactam drugs. Multiple substitutions lead to increased loop flexibility and expanded specificity in Acinetobacter baumannii carbapenemase OXA-239.,Harper TM, June CM, Taracila MA, Bonomo RA, Powers RA, Leonard DA Biochem J. 2017 Dec 11. pii: BCJ20170702. doi: 10.1042/BCJ20170702. PMID:29229762[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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