8FQU
ADC-219 in complex with boronic acid transition state inhibitor MB076
Summary for 8FQU
| Entry DOI | 10.2210/pdb8fqu/pdb |
| Descriptor | Beta-lactamase, 1-[(2R)-2-{2-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]acetamido}-2-boronoethyl]-1H-1,2,3-triazole-4-carboxylic acid, DIMETHYL SULFOXIDE, ... (4 entities in total) |
| Functional Keywords | batsi, inhibitor, acinetobacter-derived cephalosporinase, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Acinetobacter baumannii |
| Total number of polymer chains | 2 |
| Total formula weight | 82804.06 |
| Authors | Powers, R.A.,Wallar, B.J.,June, C.M.,Maurer, O.L. (deposition date: 2023-01-06, release date: 2023-07-05, Last modification date: 2023-10-25) |
| Primary citation | Powers, R.A.,June, C.M.,Fernando, M.C.,Fish, E.R.,Maurer, O.L.,Baumann, R.M.,Beardsley, T.J.,Taracila, M.A.,Rudin, S.D.,Hujer, K.M.,Hujer, A.M.,Santi, N.,Villamil, V.,Introvigne, M.L.,Prati, F.,Caselli, E.,Bonomo, R.A.,Wallar, B.J. Synthesis of a Novel Boronic Acid Transition State Inhibitor, MB076: A Heterocyclic Triazole Effectively Inhibits Acinetobacter -Derived Cephalosporinase Variants with an Expanded-Substrate Spectrum. J.Med.Chem., 66:8510-8525, 2023 Cited by PubMed Abstract: Class C -derived cephalosporinases (ADCs) represent an important target for inhibition in the multidrug-resistant pathogen . 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, , a novel heterocyclic triazole with improved plasma stability, was synthesized and inhibits seven different ADC β-lactamase variants with values <1 μM. acted synergistically in combination with multiple cephalosporins to restore susceptibility. ADC variants containing an alanine duplication in the Ω-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. PubMed: 37358467DOI: 10.1021/acs.jmedchem.3c00144 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.49 Å) |
Structure validation
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