Solution structure of an oligodeoxynucleotide containing the malondialdehyde deoxyguanosine adduct N2-(3-oxo-1-propenyl)-dG (ring-opened M1G) positioned in a (CpG)3 frameshift hotspot of the Salmonella typhimurium hisD3052 gene.
The refined solution structure for the ring-opened N2-(3-oxo-1-propenyl)-dG derivative of the malondialdehyde deoxyguanosine adduct M(1)G [3-(2'-deoxy-beta-D-erythro-pentofuranosyl)pyrimido[1, 2-a]purin-10(3H)-one] in d(ATCGCXCGGCATG) x d(CATGCCGCGCGAT) [X being N(2)-(3-oxo-1-propenyl)-dG], containing the d(CpG)(3) frameshift hotspot of the Salmonella typhimurium hisD3052 gene, is presented. When inserted into this duplex, M(1)G underwent spontaneous ring opening to N2-(3-oxo-1-propenyl)-dG. NMR analysis revealed that N2-(3-oxo-1-propenyl)-dG induced minor structural perturbations in the hisD3052 oligodeoxynucleotide. However, the stability of the duplex DNA was reduced; the N2-(3-oxo-1-propenyl)-dG-modified hisD3052 oligodeoxynucleotide exhibited a 14 degrees C decrease in T(m) relative to that of the native oligodeoxynucleotide. The modified guanine maintained stacking interactions with neighboring bases but was not Watson-Crick hydrogen bonded. A total of 13 NOEs were observed from the 3-oxo-1-propenyl moiety protons of N2-(3-oxo-1-propenyl)-dG to DNA protons. Molecular dynamics calculations, restrained by 602 distance restraints derived from experimental NOE measurements and 23 empirical distance restraints, converged with pairwise rmsd differences of <0.90 A. The sixth-root residual factor with the NMR data was 9.1 x 10(-2). The cytosine complementary to N2-(3-oxo-1-propenyl)-dG was pushed toward the major groove but maintained partial stacking interactions with its neighboring bases. The modified guanine remained in the anti conformation, while the 3-oxo-1-propenyl moiety was positioned in the minor groove of the duplex. Possible correlations between the relatively small structural perturbations induced in this DNA duplex by N2-(3-oxo-1-propenyl)-dG and the mutagenic spectrum of M(1)G are discussed.
Mao
H
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Department of Chemistry, Center in Molecular Toxicology, A. B. Hancock, Jr. Memorial Laboratory for Cancer Research, Vanderbilt University, Nashville, Tennessee 37235, USA.
Reddy
G R
GR
Marnett
L J
LJ
Stone
M P
MP
D000429:Alcohol Oxidoreductases; D001426:Bacterial Proteins / Q000235:genetics*; D018899:CpG Islands; D018736:DNA Adducts / Q000737:chemistry*; D004269:DNA, Bacterial / Q000737:chemistry; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry; D016368:Frameshift Mutation; D005798:Genes, Bacterial; D008315:Malondialdehyde / Q000737:chemistry*; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*; D011522:Protons; D011687:Purines / Q000737:chemistry; D011741:Pyrimidine Nucleosides / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry; D012486:Salmonella typhimurium / Q000235:genetics; D012996:Solutions; D013816:Thermodynamics
C090855:1,N(2)-(1,3-propano)-2'-deoxyguanosine; D001426:Bacterial Proteins; D018736:DNA Adducts; D004269:DNA, Bacterial; D009838:Oligodeoxyribonucleotides; D011522:Protons; D011687:Purines; D011741:Pyrimidine Nucleosides; D011743:Pyrimidines; D012996:Solutions; C107643:pyrimido(1,2-a)purin-10(3H)-one; D008315:Malondialdehyde; C073391:3-ribofuranosyl-pyrimido(1,2-a)purin-10(3H)-one; D000429:Alcohol Oxidoreductases; C021358:histidinol dehydrogenase; D003849:Deoxyguanosine