6tzi: Difference between revisions
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==ADC-7 in complex with boronic acid transition state inhibitor PFC_001== | ==ADC-7 in complex with boronic acid transition state inhibitor PFC_001== | ||
<StructureSection load='6tzi' size='340' side='right'caption='[[6tzi]]' scene=''> | <StructureSection load='6tzi' size='340' side='right'caption='[[6tzi]], [[Resolution|resolution]] 1.74Å' 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=6TZI OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TZI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TZI FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.744Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=P1K:phosphonooxy-[[4-[[2,2,2-tris(fluoranyl)ethylsulfonylamino]methyl]-1,2,3-triazol-1-yl]methyl]borinic+acid'>P1K</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=6tzi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tzi OCA], [https://pdbe.org/6tzi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tzi RCSB], [https://www.ebi.ac.uk/pdbsum/6tzi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tzi ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Boronic acid transition state inhibitors (BATSIs) are known reversible covalent inhibitors of serine beta-lactamases. The selectivity and high potency of specific BATSIs bearing an amide side chain mimicking the beta-lactam's amide side chain are an established and recognized synthetic strategy. Herein, we describe a new class of BATSIs where the amide group is replaced by a bioisostere triazole; these compounds were designed as molecular probes. To this end, a library of 26 alpha-triazolylmethaneboronic acids was synthesized and tested against the clinically concerning Acinetobacter-derived cephalosporinase, ADC-7. In steady state analyses, these compounds demonstrated Ki values ranging from 90 nM to 38 muM (+/-10%). Five compounds were crystallized in complex with ADC-7 beta-lactamase, and all the crystal structures reveal the triazole is in the putative amide binding site, thus confirming the triazole-amide bioisosterism. The easy synthetic access of these new inhibitors as prototype scaffolds allows the insertion of a wide range of chemical groups able to explore the enzyme binding site and provides insights on the importance of specific residues in recognition and catalysis. The best inhibitor identified, compound 6q (Ki 90 nM), places a tolyl group near Arg340, making favorable cation-pi interactions. Notably, the structure of 6q does not resemble the natural substrate of the beta-lactamase yet displays a pronounced inhibition activity, in addition to lowering the minimum inhibitory concentration (MIC) of ceftazidime against three bacterial strains expressing class C beta-lactamases. In summary, these observations validate the alpha-triazolylboronic acids as a promising template for further inhibitor design. | |||
1,2,3-Triazolylmethaneboronate: A Structure Activity Relationship Study of a Class of beta-Lactamase Inhibitors against Acinetobacter baumannii Cephalosporinase.,Caselli E, Fini F, Introvigne ML, Stucchi M, Taracila MA, Fish ER, Smolen KA, Rather PN, Powers RA, Wallar BJ, Bonomo RA, Prati F ACS Infect Dis. 2020 Jun 24. doi: 10.1021/acsinfecdis.0c00254. PMID:32502340<ref>PMID:32502340</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6tzi" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Latest revision as of 14:17, 30 October 2024
ADC-7 in complex with boronic acid transition state inhibitor PFC_001ADC-7 in complex with boronic acid transition state inhibitor PFC_001
Structural highlights
Publication Abstract from PubMedBoronic acid transition state inhibitors (BATSIs) are known reversible covalent inhibitors of serine beta-lactamases. The selectivity and high potency of specific BATSIs bearing an amide side chain mimicking the beta-lactam's amide side chain are an established and recognized synthetic strategy. Herein, we describe a new class of BATSIs where the amide group is replaced by a bioisostere triazole; these compounds were designed as molecular probes. To this end, a library of 26 alpha-triazolylmethaneboronic acids was synthesized and tested against the clinically concerning Acinetobacter-derived cephalosporinase, ADC-7. In steady state analyses, these compounds demonstrated Ki values ranging from 90 nM to 38 muM (+/-10%). Five compounds were crystallized in complex with ADC-7 beta-lactamase, and all the crystal structures reveal the triazole is in the putative amide binding site, thus confirming the triazole-amide bioisosterism. The easy synthetic access of these new inhibitors as prototype scaffolds allows the insertion of a wide range of chemical groups able to explore the enzyme binding site and provides insights on the importance of specific residues in recognition and catalysis. The best inhibitor identified, compound 6q (Ki 90 nM), places a tolyl group near Arg340, making favorable cation-pi interactions. Notably, the structure of 6q does not resemble the natural substrate of the beta-lactamase yet displays a pronounced inhibition activity, in addition to lowering the minimum inhibitory concentration (MIC) of ceftazidime against three bacterial strains expressing class C beta-lactamases. In summary, these observations validate the alpha-triazolylboronic acids as a promising template for further inhibitor design. 1,2,3-Triazolylmethaneboronate: A Structure Activity Relationship Study of a Class of beta-Lactamase Inhibitors against Acinetobacter baumannii Cephalosporinase.,Caselli E, Fini F, Introvigne ML, Stucchi M, Taracila MA, Fish ER, Smolen KA, Rather PN, Powers RA, Wallar BJ, Bonomo RA, Prati F ACS Infect Dis. 2020 Jun 24. doi: 10.1021/acsinfecdis.0c00254. PMID:32502340[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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