Binding of the antitumor drug nogalamycin to bulged DNA structures

Janet Caceres-Cortes, Andrew H.J. Wang

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19 引文 斯高帕斯(Scopus)


Defects in DNA, e.g., unpaired/bulged nucleotides, are repaired by specific repair enzymes. Understanding the dynamics and structure of DNA defects is important. Two DNA heptamers, CT(b)-GTACG and CGTACT(b)G, each containing a bulged T nucleotide embedded in the CpG step, have been studied by NMR. Both duplexes are significantly destabilized, and the bulged T remains intrahelical. Binding of the anthracycline antitumor antibiotic nogalamycin (Ng) to these two heptamers stabilizes the duplex structure. The solution structures of the 2:1 complexes of Ng-d(CT(b)GTACG) and Ng- d(CGTACT(b)G) have been determined by the NOE-restrained refinement procedure. In both structures the elongated aglycon of Ng is intercalated between base pairs, and the nogalose and aminoglucose lie in the minor and major grooves, respectively. The bulged T behaves differently upon the binding of Ng. In Ng-CT(b)GTACG wobble G6:T(b) base pairs are formed, leaving two dangling 5'-C1 nucleotides; whereas in Ng-CGTACT(b)G weak C1:T(b) base pairs are formed, leaving two dangling 3'-G6 nucleotides. Thus Ng induces the bulged T and the opposing base in the duplex to stack on the aglycon and causes the base next to T(b) to unpair, mimicking a 'frame- shift', Such structural rearrangement of a bulged DNA site title to the binding of an intercalator drug may perturb the recognition of DNA defects by repair enzymes or may cause mutation during replication.

頁(從 - 到)616-625
出版狀態已發佈 - 1月 16 1996

ASJC Scopus subject areas

  • 生物化學


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