8fqw: Difference between revisions
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==ADC-30 in complex with boronic acid transition state inhibitor MB076== | |||
<StructureSection load='8fqw' size='340' side='right'caption='[[8fqw]], [[Resolution|resolution]] 1.59Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8fqw]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Acinetobacter_baumannii Acinetobacter baumannii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8FQW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FQW 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]] 1.59Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=YDB:1-[(2R)-2-{2-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]acetamido}-2-boronoethyl]-1H-1,2,3-triazole-4-carboxylic+acid'>YDB</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=8fqw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fqw OCA], [https://pdbe.org/8fqw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fqw RCSB], [https://www.ebi.ac.uk/pdbsum/8fqw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fqw ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/A7XM81_ACIBA A7XM81_ACIBA] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Class C Acinetobacter-derived cephalosporinases (ADCs) represent an important target for inhibition in the multidrug-resistant pathogen Acinetobacter baumannii. Many ADC variants have emerged, and characterization of their structural and functional differences is essential. Equally as important is the development of compounds that inhibit all prevalent ADCs despite these differences. The boronic acid transition state inhibitor, MB076, a novel heterocyclic triazole with improved plasma stability, was synthesized and inhibits seven different ADC beta-lactamase variants with K(i) values <1 muM. MB076 acted synergistically in combination with multiple cephalosporins to restore susceptibility. ADC variants containing an alanine duplication in the Omega-loop, specifically ADC-33, exhibited increased activity for larger cephalosporins, such as ceftazidime, cefiderocol, and ceftolozane. X-ray crystal structures of ADC variants in this study provide a structural context for substrate profile differences and show that the inhibitor adopts a similar conformation in all ADC variants, despite small changes near their active sites. | |||
Synthesis of a Novel Boronic Acid Transition State Inhibitor, MB076: A Heterocyclic Triazole Effectively Inhibits Acinetobacter-Derived Cephalosporinase Variants with an Expanded-Substrate Spectrum.,Powers RA, June CM, Fernando MC, Fish ER, Maurer OL, Baumann RM, Beardsley TJ, Taracila MA, Rudin SD, Hujer KM, Hujer AM, Santi N, Villamil V, Introvigne ML, Prati F, Caselli E, Bonomo RA, Wallar BJ J Med Chem. 2023 Jul 13;66(13):8510-8525. doi: 10.1021/acs.jmedchem.3c00144. Epub , 2023 Jun 26. PMID:37358467<ref>PMID:37358467</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 8fqw" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Acinetobacter baumannii]] | |||
[[Category: Large Structures]] | |||
[[Category: June CM]] | |||
[[Category: Powers RA]] | |||
[[Category: Ruiz VJ]] | |||
[[Category: Wallar BJ]] | |||
Latest revision as of 10:16, 21 November 2024
ADC-30 in complex with boronic acid transition state inhibitor MB076ADC-30 in complex with boronic acid transition state inhibitor MB076
Structural highlights
FunctionPublication Abstract from PubMedClass C Acinetobacter-derived cephalosporinases (ADCs) represent an important target for inhibition in the multidrug-resistant pathogen Acinetobacter baumannii. Many ADC variants have emerged, and characterization of their structural and functional differences is essential. Equally as important is the development of compounds that inhibit all prevalent ADCs despite these differences. The boronic acid transition state inhibitor, MB076, a novel heterocyclic triazole with improved plasma stability, was synthesized and inhibits seven different ADC beta-lactamase variants with K(i) values <1 muM. MB076 acted synergistically in combination with multiple cephalosporins to restore susceptibility. ADC variants containing an alanine duplication in the Omega-loop, specifically ADC-33, exhibited increased activity for larger cephalosporins, such as ceftazidime, cefiderocol, and ceftolozane. X-ray crystal structures of ADC variants in this study provide a structural context for substrate profile differences and show that the inhibitor adopts a similar conformation in all ADC variants, despite small changes near their active sites. Synthesis of a Novel Boronic Acid Transition State Inhibitor, MB076: A Heterocyclic Triazole Effectively Inhibits Acinetobacter-Derived Cephalosporinase Variants with an Expanded-Substrate Spectrum.,Powers RA, June CM, Fernando MC, Fish ER, Maurer OL, Baumann RM, Beardsley TJ, Taracila MA, Rudin SD, Hujer KM, Hujer AM, Santi N, Villamil V, Introvigne ML, Prati F, Caselli E, Bonomo RA, Wallar BJ J Med Chem. 2023 Jul 13;66(13):8510-8525. doi: 10.1021/acs.jmedchem.3c00144. Epub , 2023 Jun 26. PMID:37358467[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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