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Replacement of the human topoisomerase linker domain with the plasmodial counterpart renders the enzyme camptothecin resistant

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  • Barbara Arnò, Department of Biology and Interuniversity Consortium, National Institute Biostructure and Biosystem (INBB), University of Rome, Italy
  • Ilda D'Annessa, Department of Biology and Interuniversity Consortium, National Institute Biostructure and Biosystem (INBB), University of Rome, Italy
  • Cinzia Tesauro
  • Laura Zuccaro, Department of Biology and Interuniversity Consortium, National Institute Biostructure and Biosystem (INBB), University of Rome, Italy
  • Alessio Ottaviani, Denmark
  • Birgitta R. Knudsen
  • Paola Fiorani, Institute of Translational Pharmacology, National Research Council, CNR, Italy
  • Alessandro Desideri, Department of Biology and Interuniversity Consortium, National Institute Biostructure and Biosystem (INBB), University of Rome, Italy
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.
Original languageEnglish
Article numbere68404
JournalPLOS ONE
Volume8
Issue7
Number of pages14
ISSN1932-6203
DOIs
Publication statusPublished - 2 Jul 2013

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