Crystal Structure of the OXA-48 β-Lactamase Reveals Mechanistic Diversity among Class D Carbapenemases
20 ноября 2020 года
12:34
Crystal Structure of the OXA-48 β-Lactamase Reveals Mechanistic Diversity among Class D Carbapenemases
Текст новости:
Title: Crystal Structure of the OXA-48 β-Lactamase Reveals Mechanistic Diversity among Class D Carbapenemases
Author, co-author: Docquier, Jean-Denis; Calderone, V.; De Luca, F.; Benvenuti, M.; Giuliani, F.; Bellucci, L.; Tafi, A.; Nordmann, P.; Botta, M.; Rossolini, G. M.; Mangani, S.
Abstract: 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. © 2009 Elsevier Ltd. All rights reserved.
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Keywords :
[en] CHEMBIO ; MICROBIO ; X ray crystallography ; Bacterial Proteins ; Catalytic Domain ; Computer Simulation ; Crystallography, X-Ray ; Kinetics ; Protein Structure, Quaternary ; Acinetobacter baumannii ; Enterobacteriaceae ; Negibacteria
Abstract :
[en] 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. © 2009 Elsevier Ltd. All rights reserved.
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