6pwm: Difference between revisions
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==ADC-7 in complex with Beta-lactam antibiotic ceftazidime== | ==ADC-7 in complex with Beta-lactam antibiotic ceftazidime== | ||
<StructureSection load='6pwm' size='340' side='right'caption='[[6pwm]]' scene=''> | <StructureSection load='6pwm' size='340' side='right'caption='[[6pwm]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PWM OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6PWM FirstGlance]. <br> | <table><tr><td colspan='2'>[[6pwm]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Aciba Aciba]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PWM OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6PWM FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6pwm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pwm OCA], [http://pdbe.org/6pwm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pwm RCSB], [http://www.ebi.ac.uk/pdbsum/6pwm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pwm ProSAT]</span></td></tr> | </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>, <scene name='pdbligand=GLY:GLYCINE'>GLY</scene></td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://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'>[http://proteopedia.org/fgij/fg.htm?mol=6pwm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pwm OCA], [http://pdbe.org/6pwm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pwm RCSB], [http://www.ebi.ac.uk/pdbsum/6pwm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pwm ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Extended-spectrum class C beta-lactamases have evolved to rapidly inactivate expanded spectrum cephalosporins, a class of antibiotics designed to be resistant to hydrolysis by beta-lactamase enzymes. To better understand the mechanism by which Acinetobacter-derived cephalosporinase-7 (ADC-7), a chromosomal AmpC enzyme, hydrolyzes these molecules, we determined the X-ray crystal structure of ADC-7 in an acyl-enzyme complex with the cephalosporin, ceftazidime (2.40 A), as well as in complex with a boronic acid transition state analog inhibitor that contains the R1 side chain of ceftazidime (1.67 A). In the acyl-enzyme complex, the carbonyl oxygen is situated in the oxyanion hole where it makes key stabilizing interactions with the main chain nitrogens of Ser64 and Ser315. The boronic acid O1 hydroxyl group is similarly positioned in this area. Conserved residues Gln120 and Asn152 form hydrogen bonds with the amide group of the R1 side chain in both complexes. These complexes represent two steps in the hydrolysis of expanded spectrum cephalosporins by ADC-7 and offer insight into the inhibition of ADC-7 by ceftazidime through displacement of the deacylating water molecule, as well as blocking its trajectory to the acyl carbonyl carbon. In addition, the transition state analog inhibitor, LP06, was shown to bind with high affinity to ADC-7 (K i 50 nM) and was able to restore ceftazidime susceptibility, offering the potential for optimization efforts of this type of inhibitor. | |||
Structural insights into inhibition of the Acinetobacter derived cephalosporinase ADC-7 by ceftazidime and its boronic acid transition state analog.,Curtis BN, Smolen KA, Barlow SJ, Caselli E, Prati F, Taracila MA, Bonomo RA, Wallar BJ, Powers RA Antimicrob Agents Chemother. 2020 Sep 28. pii: AAC.01183-20. doi:, 10.1128/AAC.01183-20. PMID:32988830<ref>PMID:32988830</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6pwm" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Aciba]] | |||
[[Category: Beta-lactamase]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Curtis | [[Category: Curtis, B C]] | ||
[[Category: Powers | [[Category: Powers, R A]] | ||
[[Category: Wallar | [[Category: Wallar, B J]] | ||
[[Category: Adc-7]] | |||
[[Category: Antibiotic]] | |||
[[Category: Hydrolase]] | |||
[[Category: Substrate]] | |||
Revision as of 11:05, 2 December 2020
ADC-7 in complex with Beta-lactam antibiotic ceftazidimeADC-7 in complex with Beta-lactam antibiotic ceftazidime
Structural highlights
Publication Abstract from PubMedExtended-spectrum class C beta-lactamases have evolved to rapidly inactivate expanded spectrum cephalosporins, a class of antibiotics designed to be resistant to hydrolysis by beta-lactamase enzymes. To better understand the mechanism by which Acinetobacter-derived cephalosporinase-7 (ADC-7), a chromosomal AmpC enzyme, hydrolyzes these molecules, we determined the X-ray crystal structure of ADC-7 in an acyl-enzyme complex with the cephalosporin, ceftazidime (2.40 A), as well as in complex with a boronic acid transition state analog inhibitor that contains the R1 side chain of ceftazidime (1.67 A). In the acyl-enzyme complex, the carbonyl oxygen is situated in the oxyanion hole where it makes key stabilizing interactions with the main chain nitrogens of Ser64 and Ser315. The boronic acid O1 hydroxyl group is similarly positioned in this area. Conserved residues Gln120 and Asn152 form hydrogen bonds with the amide group of the R1 side chain in both complexes. These complexes represent two steps in the hydrolysis of expanded spectrum cephalosporins by ADC-7 and offer insight into the inhibition of ADC-7 by ceftazidime through displacement of the deacylating water molecule, as well as blocking its trajectory to the acyl carbonyl carbon. In addition, the transition state analog inhibitor, LP06, was shown to bind with high affinity to ADC-7 (K i 50 nM) and was able to restore ceftazidime susceptibility, offering the potential for optimization efforts of this type of inhibitor. Structural insights into inhibition of the Acinetobacter derived cephalosporinase ADC-7 by ceftazidime and its boronic acid transition state analog.,Curtis BN, Smolen KA, Barlow SJ, Caselli E, Prati F, Taracila MA, Bonomo RA, Wallar BJ, Powers RA Antimicrob Agents Chemother. 2020 Sep 28. pii: AAC.01183-20. doi:, 10.1128/AAC.01183-20. PMID:32988830[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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