Crystal Structure of the OXA-48 β-Lactamase Reveals Mechanistic Diversity among Class D Carbapenemases

Jean Denis Docquier, Vito Calderone, Filomena De Luca, Manuela Benvenuti, Francesco Giuliani, Luca Bellucci, Andrea Tafi, Patrice Nordmann, Maurizio Botta, Gian Maria Rossolini, Stefano Mangani

Research output: Contribution to journalArticle

Abstract

Carbapenem-hydrolyzing class D β-lactamases (CHDLs) are enzymes found in important Gram-negative pathogens (mainly Acinetobacter baumannii and Enterobacteriaceae) that confer resistance to β-lactam antibiotics, and notably carbapenems. The crystal structure of the OXA-48 carbapenemase was determined at pH 7.5 and at a resolution of 1.9 Å. Surprisingly, and by contrast with OXA-24, the only other CHDL of known crystal structure, the structure of OXA-48 was similar to OXA-10, an enzyme devoid of carbapenemase activity, indicating that the hydrolysis of these compounds could depend on subtle changes in the active site region. Moreover, the active site groove of OXA-48 was different from that of OXA-24 in shape, dimensions, and charge distribution. Molecular dynamics pointed to the functional relevance of residues located in or close to the β5-β6 loop and allowed us to propose a mechanism for carbapenem hydrolysis by OXA-48.

Original languageEnglish
Pages (from-to)540-547
Number of pages8
JournalChemistry and Biology
Volume16
Issue number5
DOIs
Publication statusPublished - May 29 2009

Keywords

  • CHEMBIO
  • MICROBIO

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Molecular Biology
  • Clinical Biochemistry
  • Molecular Medicine
  • Pharmacology

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    Docquier, J. D., Calderone, V., De Luca, F., Benvenuti, M., Giuliani, F., Bellucci, L., Tafi, A., Nordmann, P., Botta, M., Rossolini, G. M., & Mangani, S. (2009). Crystal Structure of the OXA-48 β-Lactamase Reveals Mechanistic Diversity among Class D Carbapenemases. Chemistry and Biology, 16(5), 540-547. https://doi.org/10.1016/j.chembiol.2009.04.010