PortEco logo

PMID:19965760

From EcoliWiki
Jump to: navigation, search

Contents

Citation

Edwards, MJ, Flatman, RH, Mitchenall, LA, Stevenson, CE, Le, TB, Clarke, TA, McKay, AR, Fiedler, HP, Buttner, MJ, Lawson, DM and Maxwell, A (2009) A crystal structure of the bifunctional antibiotic simocyclinone D8, bound to DNA gyrase. Science 326:1415-8

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.

Links

PubMed Online version:10.1126/science.1179123

Keywords

Amino Acid Sequence; Anti-Bacterial Agents/chemistry; Anti-Bacterial Agents/metabolism; Anti-Bacterial Agents/pharmacology; Binding Sites; Coumarins/chemistry; Coumarins/metabolism; Coumarins/pharmacology; Crystallography, X-Ray; DNA Gyrase/antagonists & inhibitors; DNA Gyrase/chemistry; DNA Gyrase/genetics; DNA Gyrase/metabolism; DNA, Bacterial/metabolism; Drug Resistance, Bacterial; Escherichia coli/drug effects; Escherichia coli/enzymology; Escherichia coli/genetics; Glycosides/chemistry; Glycosides/metabolism; Glycosides/pharmacology; Ligands; Models, Molecular; Molecular Sequence Data; Molecular Weight; Mutagenesis, Site-Directed; Mutation; Protein Multimerization; Protein Structure, Tertiary

Significance

You can help EcoliWiki by summarizing why this paper is useful

Useful Materials and Methods

You can help Ecoliwiki by describing the useful materials (strains, plasmids, antibodies, etc) described in this paper.

Annotations

Gene product Qualifier GO ID GO term name Evidence Code with/from Aspect Notes Status

EcoliWiki Links

Add links to pages that link here (e.g. gene, product, method pages)

See also

References

See Help:References for how to manage references in EcoliWiki.