Structural basis for the extended substrate spectrum of CMY-10, a plasmid-encoded class C beta-lactamase
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- Title
- Structural basis for the extended substrate spectrum of CMY-10, a plasmid-encoded class C beta-lactamase
- Authors
- Kim, JY; Jung, HI; An, YJ; Hun, JH; Suh, PG; Lee, HS; Lee, SH; Cha, SS
- Date Issued
- 2006-05
- Publisher
- BLACKWELL PUBLISHING
- Abstract
- The emergence and dissemination of extended-spectrum (ES) beta-lactamases induce therapeutic failure and a lack of eradication of clinical isolates even by third-generation beta-lactam antibiotics like ceftazidime. CMY-10 is a plasmid-encoded class C beta-lactamase with a wide spectrum of substrates. Unlike the well-studied class C ES beta-lactamase from Enterobacter cloacae GC1, the Omega-loop does not affect the active site conformation and the catalytic activity of CMY-10. Instead, a three-amino-acid deletion in the R2-loop appears to be responsible for the ES activity of CMY-10. According to the crystal structure solved at 1.55 angstrom resolution, the deletion significantly widens the R2 active site, which accommodates the R2 side-chains of beta-lactam antibiotics. This observation led us to demonstrate the hydrolysing activity of CMY-10 towards imipenem with a long R2 substituent. The forced mutational analyses of P99 beta-lactamase reveal that the introduction of deletion mutations into the R2-loop is able to extend the substrate spectrum of class C non-ES beta-lactamases, which is compatible with the isolation of natural class C ES enzymes harbouring deletion mutations in the R2-loop. Consequently, the opening of the R2 active site by the deletion of some residues in the R2-loop can be considered as an operative molecular strategy of class C beta-lactamases to extend their substrate spectrum.
- Keywords
- TRANSITION-STATE ANALOG; ENTEROBACTER-CLOACAE P99; CLINICAL ISOLATE; CRYSTAL-STRUCTURE; OMEGA-LOOP; INHIBITOR DESIGN; SPECIFICITY; RESISTANCE; ACID; MUTAGENESIS
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/24054
- DOI
- 10.1111/J.1365-2958.
- ISSN
- 0950-382X
- Article Type
- Article
- Citation
- MOLECULAR MICROBIOLOGY, vol. 60, no. 4, page. 907 - 916, 2006-05
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