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Nucleic Acids Research Advance Access published online on September 8, 2006
Nucleic Acids Research, doi:10.1093/nar/gkl636
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© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Nucleic Acid Enzymes

A strand-passage conformation of DNA gyrase is required to allow the bacterial toxin, CcdB, to access its binding site

Andrew B. Smith and Anthony Maxwell*

Department of Biological Chemistry, John Innes Centre Norwich Research Park, Colney, Norwich NR4 7UH, UK

*To whom correspondence should be addressed. Tel: +44 1603 450771; Fax: +44 1603 450018; Email: tony.maxwell{at}bbsrc.ac.uk

Received June 16, 2006. Revised August 7, 2006. Accepted August 8, 2006.

DNA gyrase is the only topoisomerase able to introduce negative supercoils into DNA. Absent in humans, gyrase is a successful target for antibacterial drugs. However, increasing drug resistance is a serious problem and new agents are urgently needed. The naturally-produced Escherichia coli toxin CcdB has been shown to target gyrase by what is predicted to be a novel mechanism. CcdB has been previously shown to stabilize the gyrase ‘cleavage complex’, but it has not been shown to inhibit the catalytic reactions of gyrase. We present data showing that CcdB does indeed inhibit the catalytic reactions of gyrase by stabilization of the cleavage complex and that the GyrA C-terminal DNA-wrapping domain and the GyrB N-terminal ATPase domain are dispensable for CcdB's action. We further investigate the role of specific GyrA residues in the action of CcdB by site-directed mutagenesis; these data corroborate a model for CcdB action based on a recent crystal structure of a CcdB–GyrA fragment complex. From this work, we are now able to present a model for CcdB action that explains all previous observations relating to CcdB–gyrase interaction. CcdB action requires a conformation of gyrase that is only revealed when DNA strand passage is taking place.


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