5WAF

ADC-7 in complex with boronic acid transition state inhibitor CR192

Summary for 5WAF

• Entry DOI: 10.2210/pdb5waf/pdb
• Descriptor: Beta-lactamase, phosphonooxy-[[[4-(1~{H}-1,2,3,4-tetrazol-5-yl)-2-(trifluoromethyl)phenyl]sulfonylamino]methyl]borinic acid (3 entities in total)
• Functional Keywords: inhibitor, beta-lactamase, batsi, adc-7, antimicrobial protein, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Acinetobacter baumannii
• Total number of polymer chains: 4
• Total formula weight: 164958.18

Authors

Powers, R.A.,Wallar, B.J. (deposition date: 2017-06-26, release date: 2017-12-06, Last modification date: 2024-11-06)

Primary citation

Bouza, A.A.,Swanson, H.C.,Smolen, K.A.,VanDine, A.L.,Taracila, M.A.,Romagnoli, C.,Caselli, E.,Prati, F.,Bonomo, R.A.,Powers, R.A.,Wallar, B.J.
Structure-Based Analysis of Boronic Acids as Inhibitors of Acinetobacter-Derived Cephalosporinase-7, a Unique Class C beta-Lactamase.
ACS Infect Dis, 4:325-336, 2018

PubMed Abstract: Acinetobacter baumannii is a multidrug resistant pathogen that infects more than 12 000 patients each year in the US. Much of the resistance to β-lactam antibiotics in Acinetobacter spp. is mediated by class C β-lactamases known as Acinetobacter-derived cephalosporinases (ADCs). ADCs are unaffected by clinically used β-lactam-based β-lactamase inhibitors. In this study, five boronic acid transition state analog inhibitors (BATSIs) were evaluated for inhibition of the class C cephalosporinase ADC-7. Our goal was to explore the properties of BATSIs designed to probe the R1 binding site. K values ranged from low micromolar to subnanomolar, and circular dichroism (CD) demonstrated that each inhibitor stabilizes the β-lactamase-inhibitor complexes. Additionally, X-ray crystal structures of ADC-7 in complex with five inhibitors were determined (resolutions from 1.80 to 2.09 Å). In the ADC-7/CR192 complex, the BATSI with the lowest K (0.45 nM) and greatest Δ T (+9 °C), a trifluoromethyl substituent, interacts with Arg340. Arg340 is unique to ADCs and may play an important role in the inhibition of ADC-7. The ADC-7/BATSI complexes determined in this study shed light into the unique recognition sites in ADC enzymes and also offer insight into further structure-based optimization of these inhibitors.

PubMed: 29144724
DOI: 10.1021/acsinfecdis.7b00152

Experimental method

X-RAY DIFFRACTION (2.03 Å)