Binding of the Antitumor Drug Nogalamycin to Bulged DNA Structures

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• 作者：Janet Caceres-Cortes and Andrew H.-J. Wang
• 刊名：Biochemistry
• 出版年：1996
• 出版时间：January 16, 1996
• 年：1996
• 卷：35
• 期：2
• 页码：616 - 625
• 全文大小：533K
• 年卷期：v.35,no.2(January 16, 1996)
• ISSN：1520-4995

文摘

Defects in DNA, e.g., unpaired/bulged nucleotides, are repaired byspecific repair enzymes.Understanding the dynamics and structure of DNA defects isimportant. Two DNA heptamers, CT_bGTACG and CGTACT_bG, each containing a bulged T nucleotideembedded in the CpG step, have beenstudied by NMR. Both duplexes are significantly destabilized, andthe bulged T remains intrahelical.Binding of the anthracycline antitumor antibiotic nogalamycin (Ng)to these two heptamers stabilizes theduplex structure. The solution structures of the 2:1 complexes ofNg-d(CT_bGTACG) and Ng-d(CGTACT_bG) have been determined by the NOE-restrainedrefinement procedure. In both structuresthe elongated aglycon of Ng is intercalated between base pairs, and thenogalose and aminoglucose lie inthe minor and major grooves, respectively. The bulged T behavesdifferently upon the binding of Ng. InNg-CT_bGTACG wobble G₆:T_b basepairs are formed, leaving two dangling 5'-C₁ nucleotides;whereas inNg-CGTACT_bG weak C₁:T_b base pairsare formed, leaving two dangling 3'-G₆ nucleotides.Thus Nginduces the bulged T and the opposing base in the duplex to stack onthe aglycon and causes the basenext to T_b to unpair, mimicking a "frame-shift".Such structural rearrangement of a bulged DNA sitedueto the binding of an intercalator drug may perturb the recognition ofDNA defects by repair enzymes ormay cause mutation during replication.