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Suh, Pann-Ghill
BioSignal Network Lab (BSN)
Research Interests
  • Signal transduction, cancer, metabolism, phospholipase C

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Structural basis for the extended substrate spectrum of CMY-10, a plasmid-encoded class C beta-lactamase

Cited 55 times inthomson ciCited 53 times inthomson ci
Title
Structural basis for the extended substrate spectrum of CMY-10, a plasmid-encoded class C beta-lactamase
Author
Kim, JYJung, HIAn, YJHun, JHSuh, Pann-GhillLee, HSLee, SHCha, SS
Keywords
TRANSITION-STATE ANALOG; ENTEROBACTER-CLOACAE P99; CLINICAL ISOLATE; CRYSTAL-STRUCTURE; OMEGA-LOOP; INHIBITOR DESIGN; SPECIFICITY; RESISTANCE; ACID; MUTAGENESIS
Issue Date
200605
Publisher
WILEY-BLACKWELL
Citation
MOLECULAR MICROBIOLOGY, v.60, no.4, pp.907 - 916
Abstract
The emergence and dissemination of extended-spectrum (ES) β-lactamases induce therapeutic failure and a lack of eradication of clinical isolates even by third-generation β-lactam antibiotics like ceftazidime. CMY-10 is a plasmid-encoded class C β-lactamase with a wide spectrum of substrates. Unlike the well-studied class C ES β-lactamase from Enterobacter cloacae GC1, the Ω-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 A resolution, the deletion significantly widens the R2 active site, which accommodates the R2 side-chains of β-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 β-lactamase reveal that the introduction of deletion mutations into the R2-loop is able to extend the substrate spectrum of class C non-ES β-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 β-lactamases to extend their substrate spectrum.
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DOI
http://dx.doi.org/10.1111/j.1365-2958.2006.05146.x
ISSN
0950-382X
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