English   español  
Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/2880
Share/Impact:
Statistics
logo share SHARE logo core CORE   Add this article to your Mendeley library MendeleyBASE

Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL
Exportar a otros formatos:

Title

Crystal structure of the carbapenemase OXA-24 reveals insights into the mechanism of carbapenem hydrolysis

AuthorsRomero, Antonio ; Bou, Germán; Beceiro, Alejandro; Santillana, Elena
Keywordsβ-lactamases
Carbapenem resistance
Enzyme mechanism
Protein crystallography
Acinetobacter baumannii
Issue Date20-Mar-2007
PublisherNational Academy of Sciences (U.S.)
CitationProceedings of the National Academy of Sciences of the United States of America 2007 March 27; 104(13): 5354–5359
PMCID: 1838445
AbstractCombating bacterial resistance to β-lactams, the most widely used antibiotics, is an emergent and clinically important challenge. OXA-24 is a class D β-lactamase isolated from a multiresistant epidemic clinical strain of Acinetobacter baumannii. We have investigated how OXA-24 specifically hydrolyzes the last resort carbapenem antibiotic, and we have determined the crystal structure of OXA-24 at a resolution of 2.5 Å. The structure shows that the carbapenem's substrate specificity is determined by a hydrophobic barrier that is established through the specific arrangement of the Tyr-112 and Met-223 side chains, which define a tunnel-like entrance to the active site. The importance of these residues was further confirmed by mutagenesis studies. Biochemical and microbiological analyses of specific point mutants selected on the basis of structural criteria significantly reduced the catalytic efficiency (kcat/Km) against carbapenems, whereas the specificity for oxacillin was noticeably increased. This is the previously unrecognized crystal structure that has been obtained for a class D carbapenemase enzyme. Accordingly, this information may help to improve the development of effective new drugs to combat β-lactam resistance. More specifically, it may help to overcome carbapenem resistance in A. baumannii, probably one of the most worrying infectious threats in hospitals worldwide.
DescriptionWe thank the staff of beamline BM16 at the European Synchrotron Radiation Facility for their support, C. Fernández-Cabrera for excellent technical assistance, G. Rivas for ultracentrifugation studies, and P. Grooves and M. Sefton for critical reading of the manuscript.
URIhttp://hdl.handle.net/10261/2880
DOI10.1073/pnas.0607557104
ISSN5354–5359
Appears in Collections:(CIB) Artículos
Files in This Item:
File Description SizeFormat 
crystalstructure.pdf1,75 MBAdobe PDFThumbnail
View/Open
Show full item record
Review this work
 

Related articles:


WARNING: Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.