6v8v: Difference between revisions

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<StructureSection load='6v8v' size='340' side='right'caption='[[6v8v]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
<StructureSection load='6v8v' size='340' side='right'caption='[[6v8v]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6v8v]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6V8V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6V8V FirstGlance]. <br>
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6V8V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6V8V 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]] 1.8&#8491;</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]] 1.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CAZ:ACYLATED+CEFTAZIDIME'>CAZ</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CAZ:ACYLATED+CEFTAZIDIME'>CAZ</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=6v8v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v8v OCA], [https://pdbe.org/6v8v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6v8v RCSB], [https://www.ebi.ac.uk/pdbsum/6v8v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6v8v 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=6v8v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v8v OCA], [https://pdbe.org/6v8v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6v8v RCSB], [https://www.ebi.ac.uk/pdbsum/6v8v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6v8v ProSAT]</span></td></tr>
</table>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q9L5C7_ECOLX Q9L5C7_ECOLX]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
CTX-M beta-lactamases are widespread in Gram-negative bacterial pathogens and provide resistance to the cephalosporin cefotaxime, but not to the related antibiotic, ceftazidime. Nevertheless, variants have emerged that confer resistance to ceftazidime. Two natural mutations, causing P167S and D240G substitutions in the CTX-M enzyme, result in 10-fold increased hydrolysis of ceftazidime. Although the combination of these mutations would be predicted to increase ceftazidime hydrolysis further, the P167S/D240G combination has not been observed in a naturally occurring CTX-M variant. Here, using recombinantly expressed enzymes, minimum inhibitory concentration measurements, steady-state enzyme kinetics, and X-ray crystallography, we show that the P167S/D240G double mutant enzyme exhibits decreased ceftazidime hydrolysis, lower thermostability, and decreased protein expression levels compared with each of the single mutants, indicating negative epistasis. X-ray structures of mutant enzymes with covalently trapped ceftazidime suggested that a change of an active site Omega-loop to an open conformation accommodates ceftazidime leading to enhanced catalysis. Ten microseconds of molecular dynamics simulations further correlated Omega-loop opening with catalytic activity. We observed that the wild type and P167S/D240G variant with acylated ceftazidime both favor a closed conformation not conducive for catalysis. In contrast, the single substitutions dramatically increased the probability of open conformations. We conclude that the antagonism is due to restricting the conformation of the Omega-loop. These results reveal the importance of conformational heterogeneity of active site loops in controlling catalytic activity and directing evolutionary trajectories.
Antagonism between substitutions in beta-lactamase explains a path not taken in the evolution of bacterial drug resistance.,Brown CA, Hu L, Sun Z, Patel MP, Singh S, Porter JR, Sankaran B, Prasad BVV, Bowman GR, Palzkill T J Biol Chem. 2020 Apr 16. pii: RA119.012489. doi: 10.1074/jbc.RA119.012489. PMID:32299911<ref>PMID:32299911</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6v8v" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]]
*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Escherichia coli]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Brown CA]]
[[Category: Brown CA]]
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[[Category: Palzkill TG]]
[[Category: Palzkill TG]]
[[Category: Prasad BVV]]
[[Category: Prasad BVV]]
[[Category: Sankaran B]]

Latest revision as of 13:34, 23 October 2024

Crystal structure of CTX-M-14 E166A/P167S/D240G beta-lactamase in complex with ceftazidime-2Crystal structure of CTX-M-14 E166A/P167S/D240G beta-lactamase in complex with ceftazidime-2

Structural highlights

Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.8Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

See Also

6v8v, resolution 1.80Å

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