Single Mutation in the Linker Domain Confers Protein Flexibility and Camptothecin Resistance to Human Topoisomerase I (Articolo in rivista)

Type
Label
  • Single Mutation in the Linker Domain Confers Protein Flexibility and Camptothecin Resistance to Human Topoisomerase I (Articolo in rivista) (literal)
Anno
  • 2003-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1074/jbc.M303899200 (literal)
Alternative label
  • Fiorani P.; Bruselles A.; Falconi M.; Chillemi G.; Desideri A.; Benedetti P. (2003)
    Single Mutation in the Linker Domain Confers Protein Flexibility and Camptothecin Resistance to Human Topoisomerase I
    in The Journal of biological chemistry (Print)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Fiorani P.; Bruselles A.; Falconi M.; Chillemi G.; Desideri A.; Benedetti P. (literal)
Pagina inizio
  • 43268 (literal)
Pagina fine
  • 43275 (literal)
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  • http://www.scopus.com/inward/record.url?eid=2-s2.0-0242290326&partnerID=q2rCbXpz (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 278 (literal)
Rivista
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroFascicolo
  • 44 (literal)
Note
  • Scopu (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • Department of Biology, University of Padua, Via U. Bassi 58/B, Padua 35131, Italy; Natl. Inst. for the Phys. of Matter, Department of Biology, University of Rome Tor Vergata, Via Della Ricerca Scientifica, Rome 00133, Italy; Consorzio Interuniv. Applic. Superc., Universita e Ricerca, Via Dei Tizii 6b, Rome 00185, Italy (literal)
Titolo
  • Single Mutation in the Linker Domain Confers Protein Flexibility and Camptothecin Resistance to Human Topoisomerase I (literal)
Abstract
  • DNA topoisomerase I relaxes supercoiled DNA by the formation of a covalent intermediate in which the active-site tyrosine is transiently bound to the cleaved DNA strand. The antineoplastic agent camptothecin specifically targets DNA topoisomerase I, and several mutations have been isolated that render the enzyme camptothecin-resistant. The catalytic and structural dynamical properties of a human DNA topoisomerase I mutant in which Ala-653 in the linker domain was mutated into Pro have been investigated. The mutant is resistant to camptothecin and in the absence of the drug displays a cleavage-religation equilibrium strongly shifted toward religation. The shift is mainly because of an increase in the religation rate relative to the wild type enzyme, indicating that the unperturbed linker is involved in slowing religation. Molecular dynamics simulation indicates that the Ala to Pro mutation increases the linker flexibility allowing it to sample a wider conformational space. The increase in religation rate of the mutant, explained by means of the enhanced linker flexibility, provides an explanation for the mutant camptothecin resistance. (literal)
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