8g2t: Difference between revisions
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==CRYSTAL STRUCTURE OF THE KPC-2 D179N VARIANT IN COMPLEX WITH RELEBACTAM (IMINE HYDROLYSIS INTERMEDIATE)== | |||
<StructureSection load='8g2t' size='340' side='right'caption='[[8g2t]], [[Resolution|resolution]] 1.26Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8g2t]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Klebsiella_pneumoniae Klebsiella pneumoniae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8G2T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8G2T 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]] 1.26Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=YOZ:(2~{S},5~{R})-5-azanyl-1-methanoyl-5-oxidanyl-~{N}-piperidin-4-yl-piperidine-2-carboxamide'>YOZ</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=8g2t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8g2t OCA], [https://pdbe.org/8g2t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8g2t RCSB], [https://www.ebi.ac.uk/pdbsum/8g2t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8g2t ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/BLKPC_KLEPN BLKPC_KLEPN] Hydrolyzes carbapenems, penicillins, cephalosporins and monobactams with varying efficiency. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Klebsiella pneumoniae carbapenemase-2 (KPC-2) presents a clinical threat as this beta-lactamase confers resistance to carbapenems. Recent variants of KPC-2 in clinical isolates contribute to concerning resistance phenotypes. Klebsiella pneumoniae expressing KPC-2 D179Y acquired resistance to the ceftazidime/avibactam combination affecting both the beta-lactam and the beta-lactamase inhibitor yet has lowered minimum inhibitory concentrations for all other beta-lactams tested. Furthermore, Klebsiella pneumoniae expressing the KPC-2 D179N variant also manifested resistance to ceftazidime/avibactam yet retained its ability to confer resistance to carbapenems although significantly reduced. This structural study focuses on the inhibition of KPC-2 D179N by avibactam and relebactam and expands our previous analysis that examined ceftazidime resistance conferred by D179N and D179Y variants. Crystal structures of KPC-2 D179N soaked with avibactam and co-crystallized with relebactam were determined. The complex with avibactam reveals avibactam making several hydrogen bonds, including with the deacylation water held in place by Omega loop. These results could explain why the KPC-2 D179Y variant, which has a disordered Omega loop, has a decreased affinity for avibactam. The relebactam KPC-2 D179N complex revealed a new orientation of the diazabicyclooctane (DBO) intermediate with the scaffold piperidine ring rotated ~150 degrees from the standard DBO orientation. The density shows relebactam to be desulfated and present as an imine-hydrolysis intermediate not previously observed. The tetrahedral imine moiety of relebactam interacts with the deacylation water. The rotated relebactam orientation and deacylation water interaction could potentially contribute to KPC-mediated DBO fragmentation. These results elucidate important differences that could aid in the design of novel beta-lactamase inhibitors. | |||
Exploring avibactam and relebactam inhibition of Klebsiella pneumoniae carbapenemase D179N variant: role of the Omega loop-held deacylation water.,Alsenani TA, Viviani SL, Papp-Wallace KM, Bonomo RA, van den Akker F Antimicrob Agents Chemother. 2023 Oct 18;67(10):e0035023. doi: , 10.1128/aac.00350-23. Epub 2023 Sep 26. PMID:37750722<ref>PMID:37750722</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 8g2t" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Klebsiella pneumoniae]] | |||
[[Category: Large Structures]] | |||
[[Category: Alsenani T]] | |||
[[Category: Van den Akker F]] | |||
Latest revision as of 10:16, 21 November 2024
CRYSTAL STRUCTURE OF THE KPC-2 D179N VARIANT IN COMPLEX WITH RELEBACTAM (IMINE HYDROLYSIS INTERMEDIATE)CRYSTAL STRUCTURE OF THE KPC-2 D179N VARIANT IN COMPLEX WITH RELEBACTAM (IMINE HYDROLYSIS INTERMEDIATE)
Structural highlights
FunctionBLKPC_KLEPN Hydrolyzes carbapenems, penicillins, cephalosporins and monobactams with varying efficiency. Publication Abstract from PubMedKlebsiella pneumoniae carbapenemase-2 (KPC-2) presents a clinical threat as this beta-lactamase confers resistance to carbapenems. Recent variants of KPC-2 in clinical isolates contribute to concerning resistance phenotypes. Klebsiella pneumoniae expressing KPC-2 D179Y acquired resistance to the ceftazidime/avibactam combination affecting both the beta-lactam and the beta-lactamase inhibitor yet has lowered minimum inhibitory concentrations for all other beta-lactams tested. Furthermore, Klebsiella pneumoniae expressing the KPC-2 D179N variant also manifested resistance to ceftazidime/avibactam yet retained its ability to confer resistance to carbapenems although significantly reduced. This structural study focuses on the inhibition of KPC-2 D179N by avibactam and relebactam and expands our previous analysis that examined ceftazidime resistance conferred by D179N and D179Y variants. Crystal structures of KPC-2 D179N soaked with avibactam and co-crystallized with relebactam were determined. The complex with avibactam reveals avibactam making several hydrogen bonds, including with the deacylation water held in place by Omega loop. These results could explain why the KPC-2 D179Y variant, which has a disordered Omega loop, has a decreased affinity for avibactam. The relebactam KPC-2 D179N complex revealed a new orientation of the diazabicyclooctane (DBO) intermediate with the scaffold piperidine ring rotated ~150 degrees from the standard DBO orientation. The density shows relebactam to be desulfated and present as an imine-hydrolysis intermediate not previously observed. The tetrahedral imine moiety of relebactam interacts with the deacylation water. The rotated relebactam orientation and deacylation water interaction could potentially contribute to KPC-mediated DBO fragmentation. These results elucidate important differences that could aid in the design of novel beta-lactamase inhibitors. Exploring avibactam and relebactam inhibition of Klebsiella pneumoniae carbapenemase D179N variant: role of the Omega loop-held deacylation water.,Alsenani TA, Viviani SL, Papp-Wallace KM, Bonomo RA, van den Akker F Antimicrob Agents Chemother. 2023 Oct 18;67(10):e0035023. doi: , 10.1128/aac.00350-23. Epub 2023 Sep 26. PMID:37750722[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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