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==Structure of the avibactam-CDD-1 120 minute complex in imidazole and MPD== | ==Structure of the avibactam-CDD-1 120 minute complex in imidazole and MPD== | ||
<StructureSection load='7lnr' size='340' side='right'caption='[[7lnr]]' scene=''> | <StructureSection load='7lnr' size='340' side='right'caption='[[7lnr]], [[Resolution|resolution]] 1.83Å' 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=7LNR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LNR FirstGlance]. <br> | <table><tr><td colspan='2'>[[7lnr]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/"bacillus_difficilis"_hall_and_o'toole_1935 "bacillus difficilis" hall and o'toole 1935]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LNR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LNR FirstGlance]. <br> | ||
</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=7lnr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lnr OCA], [https://pdbe.org/7lnr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lnr RCSB], [https://www.ebi.ac.uk/pdbsum/7lnr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lnr 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=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=NXL:(2S,5R)-1-FORMYL-5-[(SULFOOXY)AMINO]PIPERIDINE-2-CARBOXAMIDE'>NXL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">blaR1_1, blaR1_4, E5F39_11445, SAMEA2239407_03320, SAMEA3374989_01677 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1496 "Bacillus difficilis" Hall and O'Toole 1935])</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=7lnr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lnr OCA], [https://pdbe.org/7lnr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lnr RCSB], [https://www.ebi.ac.uk/pdbsum/7lnr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lnr ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Class D beta-lactamases have risen to notoriety due to their wide spread in bacterial pathogens, propensity to inactivate clinically important beta-lactam antibiotics, and ability to withstand inhibition by the majority of classical beta-lactamase inhibitors. Understanding the catalytic mechanism of these enzymes is thus vitally important for the development of novel antibiotics and inhibitors active against infections caused by antibiotic-resistant bacteria. Here we report an in crystallo time-resolved study of the interaction of the class D beta-lactamase CDD-1 from Clostridioides difficile with the diazobicyclooctane inhibitor, avibactam. We show that the catalytic carboxylated lysine, a residue that is essential for both acylation and deacylation of beta-lactams, is sequestered within an internal sealed pocket of the enzyme. Time-resolved snapshots generated in this study allowed us to observe decarboxylation of the lysine and movement of CO2 and water molecules through a transient channel formed between the lysine pocket and the substrate binding site facilitated by rotation of the side chain of a conserved leucine residue. These studies provide novel insights on avibactam binding to CDD-1 and into the catalytic mechanism of class D beta-lactamases in general. | |||
In Crystallo Time-Resolved Interaction of the Clostridioides difficile CDD-1 enzyme with Avibactam Provides New Insights into the Catalytic Mechanism of Class D beta-lactamases.,Stewart NK, Toth M, Stasyuk A, Vakulenko SB, Smith CA ACS Infect Dis. 2021 Apr 28. doi: 10.1021/acsinfecdis.1c00094. PMID:33908775<ref>PMID:33908775</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7lnr" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Bacillus difficilis hall and o'toole 1935]] | |||
[[Category: Beta-lactamase]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Smith | [[Category: Smith, C A]] | ||
[[Category: Stewart | [[Category: Stewart, N K]] | ||
[[Category: Vakulenko | [[Category: Vakulenko, S B]] | ||
[[Category: Antibiotic resistance]] | |||
[[Category: Hydrolase]] | |||
[[Category: Hydrolase-inhibitor complex]] | |||
Revision as of 10:50, 25 June 2021
Structure of the avibactam-CDD-1 120 minute complex in imidazole and MPDStructure of the avibactam-CDD-1 120 minute complex in imidazole and MPD
Structural highlights
Publication Abstract from PubMedClass D beta-lactamases have risen to notoriety due to their wide spread in bacterial pathogens, propensity to inactivate clinically important beta-lactam antibiotics, and ability to withstand inhibition by the majority of classical beta-lactamase inhibitors. Understanding the catalytic mechanism of these enzymes is thus vitally important for the development of novel antibiotics and inhibitors active against infections caused by antibiotic-resistant bacteria. Here we report an in crystallo time-resolved study of the interaction of the class D beta-lactamase CDD-1 from Clostridioides difficile with the diazobicyclooctane inhibitor, avibactam. We show that the catalytic carboxylated lysine, a residue that is essential for both acylation and deacylation of beta-lactams, is sequestered within an internal sealed pocket of the enzyme. Time-resolved snapshots generated in this study allowed us to observe decarboxylation of the lysine and movement of CO2 and water molecules through a transient channel formed between the lysine pocket and the substrate binding site facilitated by rotation of the side chain of a conserved leucine residue. These studies provide novel insights on avibactam binding to CDD-1 and into the catalytic mechanism of class D beta-lactamases in general. In Crystallo Time-Resolved Interaction of the Clostridioides difficile CDD-1 enzyme with Avibactam Provides New Insights into the Catalytic Mechanism of Class D beta-lactamases.,Stewart NK, Toth M, Stasyuk A, Vakulenko SB, Smith CA ACS Infect Dis. 2021 Apr 28. doi: 10.1021/acsinfecdis.1c00094. PMID:33908775[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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