Structural insights into catalytic relevances of substrates' poses in ACC-1

Da-Woon Bae, Ye-Eun Jung, Young Jun An, Jung-Hyun Na, Sun-Shin Cha
2019 Antimicrobial Agents and Chemotherapy  
ACC-1 is a plasmid-encoded class C β-lactamase identified in clinical isolates of Klebsiella pneumoniae, Proteus mirabilis, Salmonella enterica, and Escherichia coli. 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
more » ... ong 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 C4 carboxylate and N5 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.
doi:10.1128/aac.01411-19 pmid:31451494 pmcid:PMC6811428 fatcat:ee7tfx2gzrabrhjwgcwwjzmgza