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

Lisa A. Peterson, Choua Vu, Brian E. Hingerty, Suse Broyde, Monique Cosman

Research output: Contribution to journalArticle

Abstract

The pyridyloxobutylating agents derived from metabolically activated tobacco-specific nitrosamines can covalently modify guanine bases in DNA at the O6 position. The adduct formed, O 6-[4-oxo-4-(3-pyridyl)butyl]guanine ([POB]dG), results in mutations that can lead to tumor formation, posing a significant cancer risk to humans exposed to tobacco smoke. A combined NMR-molecular mechanics computational approach was used to determine the solution structure of the [POB]dG adduct within an 11mer duplex sequence d(CCATAT-[POB]G-GCCC)·d(GGGCCATATGG). In agreement with the NMR results, the POB ligand is located in the major groove, centered between the flanking 5′-side dT·dA and the 3′-side dG·dC base pairs and thus in the plane of the modified [POB]dG·dC base pair, which is displaced slightly into the minor groove. The modified base pair in the structure adopts wobble base pairing (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 oxygen and the partner dC's second amino proton. The modified guanine purine base, partner cytosine pyrimidine base, and POB pyridyl ring form a triplex via this unusual hydrogen-bonding pattern. The phosphodiester backbone twists at the lesion site, accounting for the unusual phosphorus chemical shift differences relative to those for the control DNA duplex. The helical distortions and wobble base pairing induced by the covalent binding of POB to the O6-position of dG help explain the significant decrease of 17.6 °C in melting temperature of the modified duplex relative to the unmodified control.

Original languageEnglish (US)
Pages (from-to)13134-13144
Number of pages11
JournalBiochemistry
Volume42
Issue number45
DOIs
StatePublished - Nov 18 2003

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Guanine
Protons
DNA
Base Pairing
Hydrogen bonds
Tobacco
Hydrogen
Nuclear magnetic resonance
Nitrosamines
Molecular mechanics
Cytosine
Chemical shift
Hydrogen Bonding
Mechanics
Smoke
Phosphorus
Freezing
Melting point
Tumors
Neoplasms

ASJC Scopus subject areas

  • Biochemistry

Cite this

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. / Peterson, Lisa A.; Vu, Choua; Hingerty, Brian E.; Broyde, Suse; Cosman, Monique.

In: Biochemistry, Vol. 42, No. 45, 18.11.2003, p. 13134-13144.

Research output: Contribution to journalArticle

Peterson, Lisa A. ; Vu, Choua ; Hingerty, Brian E. ; Broyde, Suse ; Cosman, Monique. / 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. In: Biochemistry. 2003 ; Vol. 42, No. 45. pp. 13134-13144.
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title = "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",
abstract = "The pyridyloxobutylating agents derived from metabolically activated tobacco-specific nitrosamines can covalently modify guanine bases in DNA at the O6 position. The adduct formed, O 6-[4-oxo-4-(3-pyridyl)butyl]guanine ([POB]dG), results in mutations that can lead to tumor formation, posing a significant cancer risk to humans exposed to tobacco smoke. A combined NMR-molecular mechanics computational approach was used to determine the solution structure of the [POB]dG adduct within an 11mer duplex sequence d(CCATAT-[POB]G-GCCC)·d(GGGCCATATGG). In agreement with the NMR results, the POB ligand is located in the major groove, centered between the flanking 5′-side dT·dA and the 3′-side dG·dC base pairs and thus in the plane of the modified [POB]dG·dC base pair, which is displaced slightly into the minor groove. The modified base pair in the structure adopts wobble base pairing (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 oxygen and the partner dC's second amino proton. The modified guanine purine base, partner cytosine pyrimidine base, and POB pyridyl ring form a triplex via this unusual hydrogen-bonding pattern. The phosphodiester backbone twists at the lesion site, accounting for the unusual phosphorus chemical shift differences relative to those for the control DNA duplex. The helical distortions and wobble base pairing induced by the covalent binding of POB to the O6-position of dG help explain the significant decrease of 17.6 °C in melting temperature of the modified duplex relative to the unmodified control.",
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AB - The pyridyloxobutylating agents derived from metabolically activated tobacco-specific nitrosamines can covalently modify guanine bases in DNA at the O6 position. The adduct formed, O 6-[4-oxo-4-(3-pyridyl)butyl]guanine ([POB]dG), results in mutations that can lead to tumor formation, posing a significant cancer risk to humans exposed to tobacco smoke. A combined NMR-molecular mechanics computational approach was used to determine the solution structure of the [POB]dG adduct within an 11mer duplex sequence d(CCATAT-[POB]G-GCCC)·d(GGGCCATATGG). In agreement with the NMR results, the POB ligand is located in the major groove, centered between the flanking 5′-side dT·dA and the 3′-side dG·dC base pairs and thus in the plane of the modified [POB]dG·dC base pair, which is displaced slightly into the minor groove. The modified base pair in the structure adopts wobble base pairing (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 oxygen and the partner dC's second amino proton. The modified guanine purine base, partner cytosine pyrimidine base, and POB pyridyl ring form a triplex via this unusual hydrogen-bonding pattern. The phosphodiester backbone twists at the lesion site, accounting for the unusual phosphorus chemical shift differences relative to those for the control DNA duplex. The helical distortions and wobble base pairing induced by the covalent binding of POB to the O6-position of dG help explain the significant decrease of 17.6 °C in melting temperature of the modified duplex relative to the unmodified control.

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