A Crystal Structure of the Bifunctional Antibiotic Simocyclinone D8, Bound to DNA Gyrase

Edwards, Marcus J., Flatman, Ruth H., Mitchenall, Lesley A., Stevenson, Clare E. M., Le, Tung B. K., Clarke, Thomas A., McKay, Adam R., Fiedler, Hans-Peter, Buttner, Mark J., Lawson, David M. and Maxwell, Anthony (2009) A Crystal Structure of the Bifunctional Antibiotic Simocyclinone D8, Bound to DNA Gyrase. Science, 326 (5958). pp. 1415-1418. ISSN 0036-8075

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Abstract

Simocyclinones are bifunctional antibiotics that inhibit bacterial DNA gyrase by preventing DNA binding to the enzyme. We report the crystal structure of the complex formed between the N-terminal domain of the Escherichia coli gyrase A subunit and simocyclinone D8, revealing two binding pockets that separately accommodate the aminocoumarin and polyketide moieties of the antibiotic. These are close to, but distinct from, the quinolone-binding site, consistent with our observations that several mutations in this region confer resistance to both agents. Biochemical studies show that the individual moieties of simocyclinone D8 are comparatively weak inhibitors of gyrase relative to the parent compound, but their combination generates a more potent inhibitor. Our results should facilitate the design of drug molecules that target these unexploited binding pockets.

Item Type: Article
Faculty \ School: Faculty of Science > School of Biological Sciences
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Depositing User: Users 2731 not found.
Date Deposited: 24 May 2011 09:33
Last Modified: 29 Oct 2020 00:32
URI: https://ueaeprints.uea.ac.uk/id/eprint/31285
DOI: 10.1126/science.1179123

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