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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^, 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(Asp⁴²⁶Asn) and GyrB(Lys⁴⁴⁷Glu), 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.

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

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