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


ABSTRACT: ACC-1 is a plasmid-encoded class C ?-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 ? 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.

SUBMITTER: Bae DW 

PROVIDER: S-EPMC6811428 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Bae Da-Woon DW   Jung Ye-Eun YE   An Young Jun YJ   Na Jung-Hyun JH   Cha Sun-Shin SS  

Antimicrobial agents and chemotherapy 20191022 11


ACC-1 is a plasmid-encoded class C β-lactamase identified in clinical isolates of <i>Klebsiella pneumoniae</i>, <i>Proteus mirabilis</i>, <i>Salmonella enterica</i>, and <i>Escherichia coli</i> 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 l  ...[more]

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