Biophysical characterization of an indolinone inhibitor in the ATP-binding site of DNA gyrase. - Archive ouverte HAL
Journal Articles Biochemical and Biophysical Research Communications Year : 2006

Biophysical characterization of an indolinone inhibitor in the ATP-binding site of DNA gyrase.

Abstract

Fighting bacterial resistance is a challenging task in the field of medicinal chemistry. DNA gyrase represents a validated antibacterial target and has drawn much interest in recent years. By a structure-based approach we have previously discovered compound 1, an indolinone derivative, possessing inhibitory activity against DNA gyrase. In the present paper, a detailed biophysical characterization of this inhibitor is described. Using mass spectrometry, NMR spectroscopy, and fluorescence experiments we have demonstrated that compound 1 binds reversibly to the ATP-binding site of the 24 kDa N-terminal fragment of DNA gyrase B from Escherichia coli (GyrB24) with low micromolar affinity. Based on these data, a plausible molecular model of compound 1 in the active site of GyrB24 was constructed. The predicted binding mode explains the competitive inhibitory mechanism with respect to ATP and forms a useful basis for further development of potent DNA gyrase inhibitors.

Dates and versions

hal-00188088 , version 1 (15-11-2007)

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Marko Oblak, Simona Golic Grdadolnik, Miha Kotnik, Arnaud Poterszman, Robert Andrew Atkinson, et al.. Biophysical characterization of an indolinone inhibitor in the ATP-binding site of DNA gyrase.. Biochemical and Biophysical Research Communications, 2006, 349 (4), pp.1206-13. ⟨10.1016/j.bbrc.2006.08.172⟩. ⟨hal-00188088⟩
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