8fqo | pdb_00008fqo

ADC-33 in complex with boronic acid transition state inhibitor MB076

spinqualitylabelsall models 8fqo, resolution 1.83Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8fqo is a 2 chain structure with sequence from Acinetobacter baumannii. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.83Å Ligands: PO4, YDB Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A7Y407_ACIBA 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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