TY - JOUR
T1 - Crystal Structure of the OXA-48 β-Lactamase Reveals Mechanistic Diversity among Class D Carbapenemases
AU - Docquier, Jean Denis
AU - Calderone, Vito
AU - De Luca, Filomena
AU - Benvenuti, Manuela
AU - Giuliani, Francesco
AU - Bellucci, Luca
AU - Tafi, Andrea
AU - Nordmann, Patrice
AU - Botta, Maurizio
AU - Rossolini, Gian Maria
AU - Mangani, Stefano
PY - 2009/5/29
Y1 - 2009/5/29
N2 - 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.
AB - 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.
KW - CHEMBIO
KW - MICROBIO
UR - http://www.scopus.com/inward/record.url?scp=65749120570&partnerID=8YFLogxK
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U2 - 10.1016/j.chembiol.2009.04.010
DO - 10.1016/j.chembiol.2009.04.010
M3 - Article
C2 - 19477418
AN - SCOPUS:65749120570
VL - 16
SP - 540
EP - 547
JO - Chemistry and Biology
JF - Chemistry and Biology
SN - 1074-5521
IS - 5
ER -