7tc1: Difference between revisions

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<StructureSection load='7tc1' size='340' side='right'caption='[[7tc1]], [[Resolution|resolution]] 1.16&Aring;' scene=''>
<StructureSection load='7tc1' size='340' side='right'caption='[[7tc1]], [[Resolution|resolution]] 1.16&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[7tc1]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TC1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TC1 FirstGlance]. <br>
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TC1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TC1 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4D6:{(3R,6S)-2-HYDROXY-3-[(THIOPHEN-2-YLACETYL)AMINO]-1,2-OXABORINAN-6-YL}ACETIC+ACID'>4D6</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.16&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7tb7|7tb7]]</div></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4D6:{(3R,6S)-2-HYDROXY-3-[(THIOPHEN-2-YLACETYL)AMINO]-1,2-OXABORINAN-6-YL}ACETIC+ACID'>4D6</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=7tc1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tc1 OCA], [https://pdbe.org/7tc1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tc1 RCSB], [https://www.ebi.ac.uk/pdbsum/7tc1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tc1 ProSAT]</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=7tc1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tc1 OCA], [https://pdbe.org/7tc1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tc1 RCSB], [https://www.ebi.ac.uk/pdbsum/7tc1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tc1 ProSAT]</span></td></tr>
</table>
</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 carbapenemases (KPC-2 and KPC-3) present a global clinical threat, as these beta-lactamases confer resistance to carbapenems and oxyimino-cephalosporins. Recent clinically identified KPC variants with substitutions at Ambler position D179, located in the Omega loop, are resistant to the beta-lactam/beta-lactamase inhibitor combination ceftazidime-avibactam, but susceptible to meropenem-vaborbactam. To gain insights into ceftazidime-avibactam resistance conferred by D179N/Y variants of KPC-2, crystal structures of these variants were determined. The D179N KPC-2 structure revealed that the change of the carboxyl to an amide moiety at position 179 disrupted the salt bridge with R164 present in wild-type KPC-2. Additional interactions were disrupted in the Omega loop, causing a decrease in the melting temperature. Shifts originating from N179 were also transmitted toward the active site, including approximately 1-A shifts of the deacylation water and interacting residue N170. The structure of the D179Y KPC-2 beta-lactamase revealed more drastic changes, as this variant exhibited disorder of the Omega loop, with other flanking regions also being disordered. We postulate that the KPC-2 variants can accommodate ceftazidime because the Omega loop is displaced in D179Y or can be more readily displaced in D179N KPC-2. To understand why the beta-lactamase inhibitor vaborbactam is less affected by the D179 variants than avibactam, we determined the crystal structure of D179N KPC-2 in complex with vaborbactam, which revealed wild-type KPC-2-like vaborbactam-active site interactions. Overall, the structural results regarding KPC-2 D179 variants revealed various degrees of destabilization of the Omega loop that contribute to ceftazidime-avibactam resistance, possible substrate-assisted catalysis of ceftazidime, and meropenem and meropenem-vaborbactam susceptibility.


Structural Characterization of the D179N and D179Y Variants of KPC-2 beta-Lactamase: Omega-Loop Destabilization as a Mechanism of Resistance to Ceftazidime-Avibactam.,Alsenani TA, Viviani SL, Kumar V, Taracila MA, Bethel CR, Barnes MD, Papp-Wallace KM, Shields RK, Nguyen MH, Clancy CJ, Bonomo RA, van den Akker F Antimicrob Agents Chemother. 2022 Mar 28:e0241421. doi: 10.1128/aac.02414-21. PMID:35341315<ref>PMID:35341315</ref>
==See Also==
 
*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7tc1" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Beta-lactamase]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Akker, F van den]]
[[Category: Alsenani T]]
[[Category: Alsenani, T]]
[[Category: Van den Akker F]]
[[Category: Antibiotic resistance]]
[[Category: Hydrolase]]
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