The human topoisomerase 1B Arg634Ala mutation results in camptothecin resistance and loss of inter-domain motion correlation (Articolo in rivista)

Type
Label
  • The human topoisomerase 1B Arg634Ala mutation results in camptothecin resistance and loss of inter-domain motion correlation (Articolo in rivista) (literal)
Anno
  • 2013-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1016/j.bbapap.2013.09.017 (literal)
Alternative label
  • D'Annessa I.; Tesauro C.; Wang Z.; Arno B.; Zuccaro L.; Fiorani P.; Desideri A. (2013)
    The human topoisomerase 1B Arg634Ala mutation results in camptothecin resistance and loss of inter-domain motion correlation
    in Biochimica et biophysica acta. Proteins and proteomics
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • D'Annessa I.; Tesauro C.; Wang Z.; Arno B.; Zuccaro L.; Fiorani P.; Desideri A. (literal)
Pagina inizio
  • 2712 (literal)
Pagina fine
  • 2721 (literal)
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  • http://www.scopus.com/inward/record.url?eid=2-s2.0-84886046025&partnerID=q2rCbXpz (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 1834 (literal)
Rivista
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroFascicolo
  • 12 (literal)
Note
  • Scopu (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • Department of Biology and Interuniversity Consortium, National Institute Biostructure and Biosystem (INBB), University of Rome Tor Vergata, Via Della Ricerca Scientifica, Rome 00133, Italy; Institute of Translational Pharmacology, National Research Council, CNR, Via Del Fosso del Cavaliere 100, Rome 00133, Italy (literal)
Titolo
  • The human topoisomerase 1B Arg634Ala mutation results in camptothecin resistance and loss of inter-domain motion correlation (literal)
Abstract
  • Human topoisomerase 1B, the unique target of the natural anticancer compound camptothecin, catalyzes the unwinding of supercoiled DNA by introducing transient single strand nicks and providing covalent protein-DNA adducts. The functional properties and the drug reactivity of the single Arg634Ala mutant have been investigated in comparison to the wild type enzyme. The mutant is characterized by an identical relaxation and cleavage rate but it displays resistance to camptothecin as indicated by a viability assay of the yeast cells transformed with the mutated protein. The mutant also displays a very fast religation rate that is only partially reduced by the presence of the drug, suggesting that this is the main reason for its resistance. A comparative analysis of the structural-dynamical properties of the native and mutant proteins by molecular dynamics simulation indicates that mutation of Arg634 brings to a loss of motion correlation between the different domains and in particular between the linker and the C-terminal domain, containing the catalytic tyrosine residue. These results indicate that the loss of motion correlation and the drug resistance are two strongly correlated events. © 2013 Elsevier B.V. (literal)
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