8FQU

ADC-219 in complex with boronic acid transition state inhibitor MB076

8FQU の概要

• エントリーDOI: 10.2210/pdb8fqu/pdb
• 分子名称: 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)
• 機能のキーワード: batsi, inhibitor, acinetobacter-derived cephalosporinase, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Acinetobacter baumannii
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 82804.06

構造登録者

Powers, R.A.,Wallar, B.J.,June, C.M.,Maurer, O.L. (登録日: 2023-01-06, 公開日: 2023-07-05, 最終更新日: 2023-10-25)

主引用文献

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

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: 37358467
DOI: 10.1021/acs.jmedchem.3c00144

実験手法

X-RAY DIFFRACTION (1.49 Å)