Biophysical characterization of an indolinone inhibitor in the ATP-binding site of DNA gyrase.
Fiche publication
Date publication
novembre 2006
Auteurs
Membres identifiés du Cancéropôle Est :
Dr MORAS Dino, Dr POTERSZMAN Arnaud
Tous les auteurs :
Oblak M, Grdadolnik SG, Kotnik M, Poterszman A, Atkinson RA, Nierengarten H, Desplancq D, Moras D, Solmajer T
Lien Pubmed
Résumé
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.
Référence
Biochem Biophys Res Commun. 2006 Nov 3;349(4):1206-13