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Solution structures of the Bacillus cereus metallo-β-lactamase BcII and its complex with the broad spectrum inhibitor R-thiomandelic acid

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journal contribution
posted on 2013-10-04, 13:44 authored by Andreas Ioannis Karsisiotis, Christian F. Damblon, Gordon C.K. Roberts
Metallo-β-lactamases, enzymes which inactivate β-lactam antibiotics, are of increasing biological and clinical significance as a source of antibiotic resistance in pathogenic bacteria. We describe the high resolution solution NMR structures of the Bacillus cereus metallo-β-lactamase, BcII, and of its complex with R-thiomandelic acid, a broad spectrum inhibitor of metallo-β-lactamases. This is the first reported solution structure of any metallo-β-lactamase. There are differences between the solution structure of the free enzyme and previously reported crystal structures in the loops flanking the active site, which are important for substrate and inhibitor binding and catalysis. The binding of R-thiomandelic acid and the roles of active site residues are defined in detail. Changes in the enzyme structure upon inhibitor binding clarify the role of the mobile β3-β4 loop. Comparisons with other metallo-β-lactamases highlight the roles of individual amino-acid residues in the active site and the β3-β4 loop in inhibitor binding and provide information on the basis of structure-activity relationships among metallo-β-lactamase inhibitors.

Funding

This work was supported by a European Research Training Network [contract HPRN-CT- 2002-00264] and by the Biotechnology and Biological Sciences Research Council [grant number BBS/B/058855].

History

Citation

Biochemical Journal, 2013, 456 (3), pp. 397-407

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Biological Sciences/Department of Biochemistry

Version

  • VoR (Version of Record)

Published in

Biochemical Journal

Publisher

Portland Press for the Biochemical Society

issn

0264-6021

eissn

1470-8728

Copyright date

2013

Available date

2013-10-04

Publisher version

http://www.biochemj.org/bj/456/bj4560397.htm

Language

en

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