ArticleJournal of amino acids2012
Role of Flexibility in Protein-DNA-Drug Recognition: The Case of Asp677Gly-Val703Ile Topoisomerase Mutant Hypersensitive to Camptothecin.
Article in Journal of amino acids, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- In Vitro and In Silico Characterization of an Antimalarial Compound with Antitumor Activity Targeting Human DNA Topoisomerase IB.International journal of molecular sciences · 2021Article
- Natural Compounds as Therapeutic Agents: The Case of Human Topoisomerase IB.International journal of molecular sciences · 2021Review
- Topoisomerase IB: a relaxing enzyme for stressed DNA.Cancer drug resistance (Alhambra, Calif.) · 2020Review
- DNA topoisomerase I domain interactions impact enzyme activity and sensitivity to camptothecin.The Journal of biological chemistry · 2015Article
- Simulations of DNA topoisomerase 1B bound to supercoiled DNA reveal changes in the flexibility pattern of the enzyme and a secondary protein-DNA binding site.Nucleic acids research · 2014Article
- Molecular mechanism of the camptothecin resistance of Glu710Gly topoisomerase IB mutant analyzed in vitro and in silico.Molecular cancer · 2013Article
- Replacement of the human topoisomerase linker domain with the plasmodial counterpart renders the enzyme camptothecin resistant.PloS one · 2013Article
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Authors and funding
8 authors.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
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