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Antimicrobial Agents and Chemotherapy, June 2002, p. 1805-1815, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1805-1815.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Quinolone-Binding Pocket of DNA Gyrase: Role of GyrB

Jonathan Heddle,{dagger} and Anthony Maxwell*

Department of Biochemistry, University of Leicester, Leicester LE1 7RH, United Kingdom

Received 12 November 2001/ Returned for modification 28 January 2002/ Accepted 7 March 2002

DNA gyrase is a prokaryotic type II topoisomerase and a major target of quinolone antibacterials. The majority of mutations conferring resistance to quinolones arise within the quinolone resistance-determining region of GyrA close to the active site (Tyr122) where DNA is bound and cleaved. However, some quinolone resistance mutations are known to exist in GyrB. Present structural data suggest that these residues lie a considerable distance from the quinolone resistance-determining region, and it is not obvious how they affect quinolone action. We have made and purified two such mutant proteins, GyrB(Asp426->Asn) and GyrB(Lys447->Glu), and characterized them in vitro. We found that the two proteins behave similarly to GyrA quinolone-resistant proteins. We showed that the mutations exert their effect by decreasing the amount of quinolone bound to a gyrase-DNA complex. We suggest that the GyrB residues form part of a quinolone-binding pocket that includes DNA and the quinolone resistance-determining region in GyrA and that large conformational changes during the catalytic cycle of the enzyme allow these regions to come into close proximity.

* Corresponding author. Present address: Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Colney, Norwich NR4 7UH, United Kingdom. Phone: (01603) 450771. Fax: (01603) 450018. E-mail: tony.maxwell{at}bbsrc.ac.uk.

{dagger} Present address: Protein Design Laboratory, Yokohama City University, Suehiro 1-7-29, Yokohama, Kanagawa 230-0045, Japan.

Antimicrobial Agents and Chemotherapy, June 2002, p. 1805-1815, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1805-1815.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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