Structure of an oligodeoxynucleotide containing a 1,N(2)-propanodeoxyguanosine adduct positioned in a palindrome derived from the Salmonella typhimurium hisD3052 gene: Hoogsteen pairing at pH 5.2

Chem Res Toxicol. 2002 Feb;15(2):127-39. doi: 10.1021/tx0101090.


The structure of the 1,N(2)-Propanodeoxyguanosine (PdG) adduct was determined at pH 5.2 in the oligodeoxynucleotide duplex 5'-d(CGCGGTXTCCGCG)3'.5'-d(CGCGGACACCGCG)-3' (X = PdG). This sequence, referred to as the -TXT- sequence, is contained within the Salmonella typhimurium hisD3052 gene and contains a palindrome, representing a potential hotspot for frameshift mutagenesis. PdG provides a model for the primary adduct induced in DNA by malondialdehyde, the 3-(2'-deoxy-beta-D-erythro-pentofuranosyl)pyrimido[1,2-a]-purin-10(3H)-one (M(1)G) lesion. The solution structure was refined by molecular dynamics calculations restrained by a combination of NMR-derived distances and dihedral angles, using a simulated annealing protocol. PdG introduced a localized perturbation into the sequence at base pair X(7).C(20), which was pH-dependent. At neutral pH, conformational exchange resulted in spectral line broadening, and it was not possible to determine the structure. A stable structure was observed at pH 5.2 in which PdG rotated about the glycosyl bond into the syn conformation. This placed the exocyclic moiety into the major groove of the duplex. PdG formed a protonated Hoogsteen pair with nucleotide C(20) in the complementary strand. The pseudorotation of the deoxyribose at C(20) was altered to an approximately equal blend of C2'-endo and C3'-endo structures. However, these made little difference in the overall structure of the modified oligodeoxynucleotide. The structure was compared to that of PdG in the 5'-d(CGCXCGGCATG)-3'.5'-(CATGCCGCGCG)-3' sequence (the -CXC- sequence) at pH 5.8 [Singh, U. S., Moe, J. G., Reddy, G. R., Weisenseel, J. P., Marnett, L. J., and Stone, M. P. (1993) Chem. Res. Toxicol. 6, 825-836]. A sequence effect was observed. When PdG was placed into the -TXT- sequence at low pH, the structural perturbation was limited to the X(7).C(20) base pair. In contrast, when PdG was placed into the -CXC- sequence at low pH, both the modified base pair and its 3'-neighbor base pair were disrupted. The results are discussed in the context of differential outcomes for site-specific mutagenesis and replication bypass experiments when PdG was placed in the -TXT- and -CXC- sequences, respectively.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alcohol Oxidoreductases*
  • Bacterial Proteins / genetics
  • Base Pairing
  • DNA Adducts / chemistry*
  • DNA-Binding Proteins / chemistry*
  • Deoxyguanosine / analogs & derivatives*
  • Deoxyguanosine / chemistry*
  • Genes, Bacterial*
  • Hydrogen-Ion Concentration
  • Oligoribonucleotides / chemistry*
  • Salmonella typhimurium / genetics


  • Bacterial Proteins
  • DNA Adducts
  • DNA-Binding Proteins
  • Oligoribonucleotides
  • 1,N(2)-propanodeoxyguanosine
  • Alcohol Oxidoreductases
  • histidinol dehydrogenase
  • Deoxyguanosine