Quinolone-Binding Pocket of DNA Gyrase: Role of GyrB

Antimicrobial Agents and Chemotherapy - Tập 46 Số 6 - Trang 1805-1815 - 2002
Jonathan G. Heddle1, Anthony Maxwell1
1Department of Biochemistry, University of Leicester, Leicester, LE1 7RH United Kingdom

Tóm tắt

ABSTRACT 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 (Tyr 122 ) 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(Asp 426 →Asn) and GyrB(Lys 447 →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.

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Antimicrobial Agents and Chemotherapy

Tập 46 Số 6

1805-1815

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