5tg5: Difference between revisions
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==OXA-24/40 in Complex with Boronic Acid BA8== | |||
<StructureSection load='5tg5' size='340' side='right' caption='[[5tg5]], [[Resolution|resolution]] 1.75Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5tg5]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TG5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TG5 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BCT:BICARBONATE+ION'>BCT</scene>, <scene name='pdbligand=JW8:{4-[(AZETIDIN-1-YL)SULFONYL]PHENYL}BORONIC+ACID'>JW8</scene>, <scene name='pdbligand=MEE:METHANETHIOL'>MEE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ABA:ALPHA-AMINOBUTYRIC+ACID'>ABA</scene>, <scene name='pdbligand=KCX:LYSINE+NZ-CARBOXYLIC+ACID'>KCX</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5tg4|5tg4]], [[5tg6|5tg6]], [[5tg7|5tg7]]</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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5tg5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tg5 OCA], [http://pdbe.org/5tg5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tg5 RCSB], [http://www.ebi.ac.uk/pdbsum/5tg5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tg5 ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
beta-lactam antibiotics are crucial to the management of bacterial infections in the medical community. Due to overuse and misuse, clinically significant bacteria are now resistant to many commercially available antibiotics. The most widespread resistance mechanism to beta-lactams is the expression of beta-lactamase enzymes. To overcome beta-lactamase mediated resistance, inhibitors were designed to inactivate these enzymes. However, current inhibitors (clavulanic acid, tazobactam, and sulbactam) for beta-lactamases also contain the characteristic beta-lactam ring, making them susceptible to resistance mechanisms employed by bacteria. This presents a critical need for novel, non-beta-lactam inhibitors that can circumvent these resistance mechanisms. The carbapenem-hydrolyzing class D beta-lactamases (CHDLs) are of particular concern, given that they efficiently hydrolyze potent carbapenem antibiotics. Unfortunately, these enzymes are not inhibited by clinically available beta-lactamase inhibitors, nor are they effectively inhibited by the newest, non-beta-lactam inhibitor, avibactam. Boronic acids are known transition state analog inhibitors of class A and C beta-lactamases, and are not extensively characterized as inhibitors of class D beta-lactamases. Importantly, boronic acids provide a novel way to potentially inhibit class D beta-lactamases. Sixteen boronic acids were selected and tested for inhibition of the CHDL OXA-24/40. Several compounds were identified as effective inhibitors of OXA-24/40, with Ki values as low as 5 muM. The X-ray crystal structures of OXA-24/40 in complex with BA3, BA4, BA8, and BA16 were determined and revealed the importance of interactions with hydrophobic residues Tyr112 and Trp115. These boronic acids serve as progenitors in optimization efforts of a novel series of inhibitors for class D beta-lactamases. This article is protected by copyright. All rights reserved. | |||
Exploring the potential of boronic acids as inhibitors of OXA-24/40 beta-lactamase.,Werner JP, Mitchell JM, Taracila MA, Bonomo RA, Powers RA Protein Sci. 2016 Dec 20. doi: 10.1002/pro.3100. PMID:27997706<ref>PMID:27997706</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Mitchell, J | <div class="pdbe-citations 5tg5" style="background-color:#fffaf0;"></div> | ||
[[Category: Werner, J | == References == | ||
[[Category: | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Beta-lactamase]] | |||
[[Category: Mitchell, J M]] | |||
[[Category: Powers, R A]] | |||
[[Category: Werner, J P]] | |||
[[Category: Complex]] | |||
[[Category: Hydrolase-hydrolase inhibitor complex]] | |||
[[Category: Inhibitor]] | |||
[[Category: Lactamase]] | |||
[[Category: Oxa]] | |||
Revision as of 19:38, 18 January 2017
OXA-24/40 in Complex with Boronic Acid BA8OXA-24/40 in Complex with Boronic Acid BA8
Structural highlights
Publication Abstract from PubMedbeta-lactam antibiotics are crucial to the management of bacterial infections in the medical community. Due to overuse and misuse, clinically significant bacteria are now resistant to many commercially available antibiotics. The most widespread resistance mechanism to beta-lactams is the expression of beta-lactamase enzymes. To overcome beta-lactamase mediated resistance, inhibitors were designed to inactivate these enzymes. However, current inhibitors (clavulanic acid, tazobactam, and sulbactam) for beta-lactamases also contain the characteristic beta-lactam ring, making them susceptible to resistance mechanisms employed by bacteria. This presents a critical need for novel, non-beta-lactam inhibitors that can circumvent these resistance mechanisms. The carbapenem-hydrolyzing class D beta-lactamases (CHDLs) are of particular concern, given that they efficiently hydrolyze potent carbapenem antibiotics. Unfortunately, these enzymes are not inhibited by clinically available beta-lactamase inhibitors, nor are they effectively inhibited by the newest, non-beta-lactam inhibitor, avibactam. Boronic acids are known transition state analog inhibitors of class A and C beta-lactamases, and are not extensively characterized as inhibitors of class D beta-lactamases. Importantly, boronic acids provide a novel way to potentially inhibit class D beta-lactamases. Sixteen boronic acids were selected and tested for inhibition of the CHDL OXA-24/40. Several compounds were identified as effective inhibitors of OXA-24/40, with Ki values as low as 5 muM. The X-ray crystal structures of OXA-24/40 in complex with BA3, BA4, BA8, and BA16 were determined and revealed the importance of interactions with hydrophobic residues Tyr112 and Trp115. These boronic acids serve as progenitors in optimization efforts of a novel series of inhibitors for class D beta-lactamases. This article is protected by copyright. All rights reserved. Exploring the potential of boronic acids as inhibitors of OXA-24/40 beta-lactamase.,Werner JP, Mitchell JM, Taracila MA, Bonomo RA, Powers RA Protein Sci. 2016 Dec 20. doi: 10.1002/pro.3100. PMID:27997706[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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