Carbapenem-hydrolyzing class D beta-lactamases (CHDLs) are enzymes found in important Gram-negative pathogens (mainly Acinetobacter baumannii and Enterobacteriaceae) that confer resistance to beta-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 A. 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 beta5-beta6 loop and allowed us to propose a mechanism for carbapenem hydrolysis by OXA-48.

Docquier, J.D., Calderone, V., DE LUCA, F., Benvenuti, M., Giuliani, F., Bellucci, L., et al. (2009). Crystal structure of the OXA-48 beta-lactamase reveals mechanistic diversity among class D carbapenemases. CHEMISTRY & BIOLOGY, 16(5), 540-547 [10.1016/j.chembiol.2009.04.010].

Crystal structure of the OXA-48 beta-lactamase reveals mechanistic diversity among class D carbapenemases.

DOCQUIER, JEAN DENIS;DE LUCA, FILOMENA;BENVENUTI, MANUELA;TAFI, ANDREA;BOTTA, MAURIZIO;ROSSOLINI, GIAN MARIA;MANGANI, STEFANO
2009-01-01

Abstract

Carbapenem-hydrolyzing class D beta-lactamases (CHDLs) are enzymes found in important Gram-negative pathogens (mainly Acinetobacter baumannii and Enterobacteriaceae) that confer resistance to beta-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 A. 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 beta5-beta6 loop and allowed us to propose a mechanism for carbapenem hydrolysis by OXA-48.
Docquier, J.D., Calderone, V., DE LUCA, F., Benvenuti, M., Giuliani, F., Bellucci, L., et al. (2009). Crystal structure of the OXA-48 beta-lactamase reveals mechanistic diversity among class D carbapenemases. CHEMISTRY & BIOLOGY, 16(5), 540-547 [10.1016/j.chembiol.2009.04.010].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/26576
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