Structural Insights into Catalytic Relevances of Substrate Poses in ACC-1
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Title
- Structural Insights into Catalytic Relevances of Substrate Poses in ACC-1
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Author(s)
- Bae, Da-Woon; Jung, Ye-Eun; An, Young Jun; Na, Jung-Hyun; Cha, Sun-Shin
- KIOST Author(s)
- An, Young Jun(안영준)
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Alternative Author(s)
- 안영준
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Publication Year
- 2019-11
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Abstract
- 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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ISSN
- 0066-4804
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URI
- https://sciwatch.kiost.ac.kr/handle/2020.kiost/470
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DOI
- 10.1128/AAC.01411-19
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Bibliographic Citation
- ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, v.63, no.11, 2019
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Publisher
- AMER SOC MICROBIOLOGY
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Subject
- AMPC BETA-LACTAMASE; KLEBSIELLA-PNEUMONIAE; ESCHERICHIA-COLI; RESISTANCE; SPECTRUM; INHIBITOR; CEPHALOSPORINASES; MECHANISMS
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Keywords
- crystal structures; ACC-1 class C beta-lactamase; adenylylation; acyl-enzyme complex; cefotaxime; cefoxitin
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Type
- Article
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Language
- English
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Document Type
- Article
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