Solution Structure of an O6-[4-oxo-4-(3-Pyridyl)butyl]guanine Adduct in an 11mer DNA Duplex: Evidence for Formation of a Base Triplex

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• 作者：Lisa A. Peterson ; Choua Vu ; Brian E. Hingerty ; Suse Broyde ; and Monique Cosman
• 刊名：Biochemistry
• 出版年：2003
• 出版时间：November 18, 2003
• 年：2003
• 卷：42
• 期：45
• 页码：13134 - 13144
• 全文大小：414K
• 年卷期：v.42,no.45(November 18, 2003)
• ISSN：1520-4995

文摘

The pyridyloxobutylating agents derived from metabolically activated tobacco-specificnitrosamines can covalently modify guanine bases in DNA at the O⁶ position. The adduct formed, O⁶-[4-oxo-4-(3-pyridyl)butyl]guanine ([POB]dG), results in mutations that can lead to tumor formation, posinga significant cancer risk to humans exposed to tobacco smoke. A combined NMR-molecular mechanicscomputational approach was used to determine the solution structure of the [POB]dG adduct within an11mer duplex sequence d(CCATAT-[POB]G-GCCC)·d(GGGCCATATGG). In agreement with the NMRresults, the POB ligand is located in the major groove, centered between the flanking 5'-side dT·dA andthe 3'-side dG·dC base pairs and thus in the plane of the modified [POB]dG·dC base pair, which isdisplaced slightly into the minor groove. The modified base pair in the structure adopts wobble basepairing (hydrogen bonds between [POB]dG(N1) and dC(NH4) amino proton and between [POB]dG(NH2) amino proton and dC(N3)). A hydrogen bond appears to occur between the POB carbonyl oxygenand the partner dC's second amino proton. The modified guanine purine base, partner cytosine pyrimidinebase, and POB pyridyl ring form a triplex via this unusual hydrogen-bonding pattern. The phosphodiesterbackbone twists at the lesion site, accounting for the unusual phosphorus chemical shift differences relativeto those for the control DNA duplex. The helical distortions and wobble base pairing induced by thecovalent binding of POB to the O⁶-position of dG help explain the significant decrease of 17.6 C inmelting temperature of the modified duplex relative to the unmodified control.