Structural Role of Uracil DNA Glycosylase for the Recognition of Uracil in DNA Duplexes. Clues from Atomistic Simulations (Articolo in rivista)

Type
Label
  • Structural Role of Uracil DNA Glycosylase for the Recognition of Uracil in DNA Duplexes. Clues from Atomistic Simulations (Articolo in rivista) (literal)
Anno
  • 2013-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1021/ci4001647 (literal)
Alternative label
  • Franco, Duvan; Sgrignani, Jacopo; Bussi, Giovanni; Magistrato, Alessandra (2013)
    Structural Role of Uracil DNA Glycosylase for the Recognition of Uracil in DNA Duplexes. Clues from Atomistic Simulations
    in Journal of chemical information and modeling
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Franco, Duvan; Sgrignani, Jacopo; Bussi, Giovanni; Magistrato, Alessandra (literal)
Pagina inizio
  • 1371 (literal)
Pagina fine
  • 1387 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 53 (literal)
Rivista
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#pagineTotali
  • 17 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroFascicolo
  • 6 (literal)
Note
  • ISI Web of Science (WOS) (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • International School for Advanced Studies; International School for Advanced Studies (literal)
Titolo
  • Structural Role of Uracil DNA Glycosylase for the Recognition of Uracil in DNA Duplexes. Clues from Atomistic Simulations (literal)
Abstract
  • In the first stage of the base excision repair pathway the enzyme uracil DNA glycosylase (UNG) recognizes and excises uracil (U) from DNA filaments. U repair is believed to occur via a multistep base-flipping process, through which the damaged U base is initially detected and then engulfed into the enzyme active site, where it is cleaved. The subtle recognition mechanism by which UNG discriminates between U and the other similar pyrimidine nucleobases is still a matter of active debate. Detailed structural information on the different steps of the base-flipping pathway may provide insights on it. However, to date only two intermediates have been trapped crystallographically thanks to chemical modifications of the target and/or of its complementary base. Here, we performed force-field based molecular dynamics (MD) simulations to explore the structural and dynamical properties of distinct UNG/dsDNA adducts, containing A:U, A:T, G:U, or G:C base pairs, at different stages of the base-flipping pathway. Our simulations reveal that if U is present in the DNA sequence a short-lived extra-helical (EH) intermediate exists. This is stabilized by a water-mediated H-bond network, which connects U with His148, a residue pointed out by mutational studies to play a key role for U recognition and catalysis. Moreover, in this EH intermediate, UNG induces a remarkable overall axis bend to DNA. We believe this aspect may facilitate the flipping of U, with respect to other similar nucleobases, in the latter art of the base-extrusion process. In fact, a large DNA bend has been demonstrated to be associated with a lowering of the free energy barrier for base-flipping. A detailed comparison of our results with partially flipped intermediates identified crystallographically or computationally for other base-flipping enzymes allows us to validate our results and to formulate hypothesis on the recognition mechanism of LING. Our study Provides a first ground for a detailed understanding of the LING repair pathway, which is necessary to devise new pharmaceutical strategies for targeting DNA-related pathologies. (literal)
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