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

Jae Young Kim, Ha Il Jung, Young Jun An, Jung Hun Lee, So Jung Kim, Seok Hoon Jeong, Kye Joon Lee, Pann Ghill Suh, Heung Soo Lee, Sang Hee Lee, Sun Shin Cha

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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 Å 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.

Original languageEnglish
Pages (from-to)907-916
Number of pages10
JournalMolecular Microbiology
Volume60
Issue number4
DOIs
Publication statusPublished - 2006 May 1

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Molecular Biology

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    Kim, J. Y., Jung, H. I., An, Y. J., Lee, J. H., Kim, S. J., Jeong, S. H., Lee, K. J., Suh, P. G., Lee, H. S., Lee, S. H., & Cha, S. S. (2006). Structural basis for the extended substrate spectrum of CMY-10, a plasmid-encoded class C β-lactamase. Molecular Microbiology, 60(4), 907-916. https://doi.org/10.1111/j.1365-2958.2006.05146.x