Crystal structure of the OXA-48 beta-lactamase reveals mechanistic diversity among class D carbapenemases.
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
Jean-Denis
JD
Dipartimento di Biologia Molecolare, Università di Siena, Italy.
Calderone
Vito
V
De Luca
Filomena
F
Benvenuti
Manuela
M
Giuliani
Francesco
F
Bellucci
Luca
L
Tafi
Andrea
A
Nordmann
Patrice
P
Botta
Maurizio
M
Rossolini
Gian Maria
GM
Mangani
Stefano
S
D001426:Bacterial Proteins / Q000737:chemistry / Q000145:classification; D020134:Catalytic Domain; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D007700:Kinetics; D020836:Protein Structure, Quaternary; D001618:beta-Lactamases / Q000737:chemistry* / Q000145:classification
D001426:Bacterial Proteins; D001618:beta-Lactamases; C063912:carbapenemase