Role of Flexibility in Protein-DNA-Drug Recognition: The Case of Asp677Gly-Val703Ile Topoisomerase Mutant Hypersensitive to Camptothecin. (19th January 2012)

• Record Type: Journal Article
• Authors: D'Annessa, Ilda; Tesauro, Cinzia; Fiorani, Paola; Chillemi, Giovanni; Castelli, Silvia; Vassallo, Oscar; Capranico, Giovanni; Desideri, Alessandro
• Other Names: Vrielink Alice Academic Editor.
• Is Part Of: Journal of amino acids. Volume 2012(2012)
• Publication Date: 2012-01-19
• Subjects: Amino acids -- Periodicals; Amino Acids; Amino acids; Electronic journals; Periodical; Periodicals; 612.015756
• DOI: 10.1155/2012/206083
• Languages: English
• ISSNs: 2090-0404

Abstract

Abstract : Topoisomerases I are ubiquitous enzymes that control DNA topology within the cell. They are the unique target of the antitumor drug camptothecin that selectively recognizes the DNA-topoisomerase covalent complex and reversibly stabilizes it. The biochemical and structural-dynamical properties of the Asp677Gly-Val703Ile double mutant with enhanced CPT sensitivity have been investigated. The mutant displays a lower religation rate of the DNA substrate when compared to the wild-type protein. Analyses of the structural dynamical properties by molecular dynamics simulation show that the mutant has reduced flexibility and an active site partially destructured at the level of the Lys532 residue. These results demonstrate long-range communication mechanism where reduction of the linker flexibility alters the active site geometry with the consequent lowering of the religation rate and increase in drug sensitivity.