3ni9: Difference between revisions
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==GES-2 carbapenemase apo form== | ==GES-2 carbapenemase apo form== | ||
<StructureSection load='3ni9' size='340' side='right' caption='[[3ni9]], [[Resolution|resolution]] 2.00Å' scene=''> | <StructureSection load='3ni9' size='340' side='right'caption='[[3ni9]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3ni9]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3ni9]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa Pseudomonas aeruginosa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3NI9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NI9 FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> | ||
<tr id=' | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</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=3ni9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ni9 OCA], [https://pdbe.org/3ni9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ni9 RCSB], [https://www.ebi.ac.uk/pdbsum/3ni9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ni9 ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/BLAG2_PSEAI BLAG2_PSEAI] Extended-spectrum beta-lactamase (ESBL) which confers resistance to penicillins, as well as first, third and fourth-generation cephalosporins (PubMed:11502535, PubMed:19656947, PubMed:20696873, PubMed:21220532). Has modest carbapenem-hydrolyzing activity (PubMed:11502535, PubMed:19656947, PubMed:25485972). Has cefotaxime-hydrolyzing activity (PubMed:11502535, PubMed:19656947).<ref>PMID:11502535</ref> <ref>PMID:19656947</ref> <ref>PMID:20696873</ref> <ref>PMID:21220532</ref> <ref>PMID:25485972</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Carbapenems are the last resort antibiotics for treatment of life-threatening infections. The GES beta-lactamases are important contributors to carbapenem resistance in clinical bacterial pathogens. A single amino acid difference at position 170 of the GES-1, GES-2, and GES-5 enzymes is responsible for the expansion of their substrate profile to include carbapenem antibiotics. This highlights the increasing need to understand the mechanisms by which the GES beta-lactamases function to aid in development of novel therapeutics. We demonstrate that the catalytic efficiency of the enzymes with carbapenems meropenem, ertapenem, and doripenem progressively increases (100-fold) from GES-1 to -5, mainly due to an increase in the rate of acylation. The data reveal that while acylation is rate limiting for GES-1 and GES-2 for all three carbapenems, acylation and deacylation are indistinguishable for GES-5. The ertapenem-GES-2 crystal structure shows that only the core structure of the antibiotic interacts with the active site of the GES-2 beta-lactamase. The identical core structures of ertapenem, doripenem, and meropenem are likely responsible for the observed similarities in the kinetics with these carbapenems. The lack of a methyl group in the core structure of imipenem may provide a structural rationale for the increase in turnover of this carbapenem by the GES beta-lactamases. Our data also show that in GES-2 an extensive hydrogen-bonding network between the acyl-enzyme complex and the active site water attenuates activation of this water molecule, which results in poor deacylation by this enzyme. | |||
Kinetic and Structural Requirements for Carbapenemase Activity in GES-Type beta-Lactamases.,Stewart NK, Smith CA, Frase H, Black DJ, Vakulenko SB Biochemistry. 2014 Dec 22. PMID:25485972<ref>PMID:25485972</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3ni9" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Beta-lactamase|Beta-lactamase]] | *[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Pseudomonas aeruginosa]] | [[Category: Pseudomonas aeruginosa]] | ||
[[Category: Frase | [[Category: Frase H]] | ||
[[Category: Smith | [[Category: Smith CA]] | ||
[[Category: Toth | [[Category: Toth M]] | ||
[[Category: Vakulenko | [[Category: Vakulenko SB]] | ||
Latest revision as of 13:13, 6 November 2024
GES-2 carbapenemase apo formGES-2 carbapenemase apo form
Structural highlights
FunctionBLAG2_PSEAI Extended-spectrum beta-lactamase (ESBL) which confers resistance to penicillins, as well as first, third and fourth-generation cephalosporins (PubMed:11502535, PubMed:19656947, PubMed:20696873, PubMed:21220532). Has modest carbapenem-hydrolyzing activity (PubMed:11502535, PubMed:19656947, PubMed:25485972). Has cefotaxime-hydrolyzing activity (PubMed:11502535, PubMed:19656947).[1] [2] [3] [4] [5] Publication Abstract from PubMedCarbapenems are the last resort antibiotics for treatment of life-threatening infections. The GES beta-lactamases are important contributors to carbapenem resistance in clinical bacterial pathogens. A single amino acid difference at position 170 of the GES-1, GES-2, and GES-5 enzymes is responsible for the expansion of their substrate profile to include carbapenem antibiotics. This highlights the increasing need to understand the mechanisms by which the GES beta-lactamases function to aid in development of novel therapeutics. We demonstrate that the catalytic efficiency of the enzymes with carbapenems meropenem, ertapenem, and doripenem progressively increases (100-fold) from GES-1 to -5, mainly due to an increase in the rate of acylation. The data reveal that while acylation is rate limiting for GES-1 and GES-2 for all three carbapenems, acylation and deacylation are indistinguishable for GES-5. The ertapenem-GES-2 crystal structure shows that only the core structure of the antibiotic interacts with the active site of the GES-2 beta-lactamase. The identical core structures of ertapenem, doripenem, and meropenem are likely responsible for the observed similarities in the kinetics with these carbapenems. The lack of a methyl group in the core structure of imipenem may provide a structural rationale for the increase in turnover of this carbapenem by the GES beta-lactamases. Our data also show that in GES-2 an extensive hydrogen-bonding network between the acyl-enzyme complex and the active site water attenuates activation of this water molecule, which results in poor deacylation by this enzyme. Kinetic and Structural Requirements for Carbapenemase Activity in GES-Type beta-Lactamases.,Stewart NK, Smith CA, Frase H, Black DJ, Vakulenko SB Biochemistry. 2014 Dec 22. PMID:25485972[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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