Structural Insights into Catalytic Relevances of Substrate Poses in ACC-1
- 주제(키워드) crystal structures , ACC-1 class C beta-lactamase , adenylylation , acyl-enzyme complex , cefotaxime , cefoxitin
- 주제(기타) Microbiology
- 주제(기타) Pharmacology & Pharmacy
- 등재 SCIE, SCOPUS
- OA유형 Green Published
- 발행기관 AMER SOC MICROBIOLOGY
- 발행년도 2019
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000162196
- 본문언어 영어
- Published As http://dx.doi.org/10.1128/AAC.01411-19
- PubMed https://pubmed.ncbi.nlm.nih.gov/31451494
초록/요약
ACC-1 is a plasmid-encoded class C beta-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 Omega 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.
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