Structural Insights into Catalytic Relevances of Substrate Poses in ACC-1

• Published in: Antimicrobial agents and chemotherapy 2019-11, Vol.63 (11)
• Main Authors: Bae, Da-Woon, Jung, Ye-Eun, An, Young Jun, Na, Jung-Hyun, Cha, Sun-Shin
• Format: Article
• Language: English
• Subjects: Bacteria; Bacterial Proteins; Mechanisms of Resistance
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01411-19

ACC-1 is a plasmid-encoded class C β-lactamase identified in clinical isolates of , , , and ACC-1-producing bacteria are susceptible to cefoxitin, whereas they are resistant to oxyimino cephalosporins. Here, we depict crystal structures of apo ACC-1, adenylylated ACC-1, and acylated ACC-1 complexed with cefotaxime and cefoxitin. ACC-1 has noteworthy structural alterations in the R2 loop, the Ω loop, and the Phe119 loop located along the active-site rim. The adenylate covalently bonded to the nucleophilic serine reveals a tetrahedral phosphorus mimicking the deacylation transition state. Cefotaxime in ACC-1 has a proper conformation for the substrate-assisted catalysis in that its C-4 carboxylate and N-5 nitrogen are adequately located to facilitate the deacylation reaction. In contrast, cefoxitin in ACC-1 has a distinct conformation, in which those functional groups cannot contribute to catalysis. Furthermore, the orientation of the deacylating water relative to the acyl carbonyl group in ACC-1 is unfavorable for nucleophilic attack.