Mechanism of inhibition of DNA gyrase by quinolone antibacterials: a cooperative drug-DNA binding model

• Published in: Biochemistry (Easton) Vol. 28; no. 9; pp. 3886 - 3894
• Main Authors: Shen, Linus L, Mitscher, Lester A, Sharma, Padam N, O'Donnell, T. J, Chu, Daniel W. T, Cooper, Curt S, Rosen, Terry, Pernet, Andre G
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 02.05.1989
• Subjects: Anti-Bacterial Agents - pharmacology; DNA - metabolism; DNA, Bacterial - metabolism; Models, Molecular; Molecular Conformation; Nalidixic Acid - pharmacology; Nucleic Acid Conformation; Protein Conformation; Quinolones - pharmacology; Structure-Activity Relationship; Topoisomerase II Inhibitors
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi00435a039

We have proposed a cooperative quinolone-DNA binding model for the inhibition of DNA gyrase. The essential feature of the model is that bound gyrase induces a specific quinolone binding site in the relaxed DNA substrate in the presence of ATP. The binding affinity and specificity are derived from two unique and equally important functional features: the specific conformation of the proposed single-stranded DNA pocket induced by the enzyme and the unique self-association phenomenon (from which the cooperativity is derived) of the drug molecules to fit the binding pocket with a high degree of flexibility. Supporting evidence for and implications of this model are provided.