A Crystal Structure of the Bifunctional Antibiotic Simocyclinone D8, Bound to DNA Gyrase
- Marcus J. Edwards1,
- Ruth H. Flatman1,
- Lesley A. Mitchenall1,
- Clare E.M. Stevenson1,
- Tung B.K. Le2,
- Thomas A. Clarke3,
- Adam R. McKay4,
- Hans-Peter Fiedler5,
- Mark J. Buttner2,
- David M. Lawson1 and
- Anthony Maxwell1,*
- 1Department of Biological Chemistry, John Innes Centre, Colney, Norwich NR4 7UH, UK.
- 2Department of Molecular Microbiology, John Innes Centre, Colney, Norwich NR4 7UH, UK.
- 3School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK.
- 4Department of Chemistry, University College London, 20 Gordon St, London WC1H 0AJ, UK.
- 5Mikrobiologisches Institut, Eberhard-Karls-Universität Tübingen, Auf der Morgenstelle 28, D-72076 Tübingen, Germany.
- *To whom correspondence should be addressed. E-mail: tony.maxwell{at}bbsrc.ac.uk
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.
