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- Title
Replacement of the Human Topoisomerase Linker Domain with the Plasmodial Counterpart Renders the Enzyme Camptothecin Resistant.
- Authors
Arnò, Barbara; D’Annessa, Ilda; Tesauro, Cinzia; Zuccaro, Laura; Ottaviani, Alessio; Knudsen, Birgitta; Fiorani, Paola; Desideri, Alessandro
- Abstract
A human/plasmodial hybrid enzyme, generated by swapping the human topoisomerase IB linker domain with the corresponding domain of the Plasmodium falciparum enzyme, has been produced and characterized. The hybrid enzyme displays a relaxation activity comparable to the human enzyme, but it is characterized by a much faster religation rate. The hybrid enzyme is also camptothecin resistant. A 3D structure of the hybrid enzyme has been built and its structural-dynamical properties have been analyzed by molecular dynamics simulation. The analysis indicates that the swapped plasmodial linker samples a conformational space much larger than the corresponding domain in the human enzyme. The large linker conformational variability is then linked to important functional properties such as an increased religation rate and a low drug reactivity, demonstrating that the linker domain has a crucial role in the modulation of the topoisomerase IB activity.
- Subjects
DNA topoisomerases; CAMPTOTHECIN; DRUG resistance; HYBRID enzymes; PROTOZOAN enzymes; PLASMODIUM falciparum; MOLECULAR dynamics
- Publication
PLoS ONE, 2013, Vol 8, Issue 7, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0068404