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|Title:||Crystal structure of the OXA-48 beta-lactamase reveals mechanistic diversity among class D carbapenemases.||Authors:||Docquier, JEAN DENIS
DE LUCA, Filomena
Rossolini, GIAN MARIA
|Keywords:||Antimicrobial resistance; beta-lactamases; carbapenemases; X-ray protein crystallography; protein structure and function||Issue Date:||2009||Project:||None||Journal:||CHEMISTRY & BIOLOGY||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.
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