Crystal Structure of the OXA-48 β-Lactamase Reveals Mechanistic Diversity among Class D Carbapenemases
2009; Elsevier BV; Volume: 16; Issue: 5 Linguagem: Inglês
10.1016/j.chembiol.2009.04.010
ISSN1879-1301
AutoresJean‐Denis Docquier, V. Calderone, Filomena De Luca, Manuela Benvenuti, Francesco Giuliani, Luca Bellucci, Andrea Tafi, Patrice Nordmann, Maurizio Botta, Gian María Rossolini, Stefano Mangani,
Tópico(s)Bacterial Genetics and Biotechnology
ResumoCarbapenem-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.
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