Crystal and solution structures of d(CGC[e6G]AATTCGCG)-Drug complexes reveal conformational polymorphism of O6-Ethyl-Guanine

Cytosine base pair

M. Sriram, Danzhou Yang, Y. G. Gao, A. H J Wang

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

O6-ethyl-guanine (e6G) is a relatively persistent alkylation lesion caused by the exposure of DNA to carcinogen N-ethyl-N-nitrosourea. We have studied the structural consequences of the e6G incorporation in DNA by X-ray crystallography and NMR. We have obtained crystals of the modified DNA dodecamer d(CGC[e6G]AATTCGCG) complexed to several minor groove binding drugs including Hoechst 33258, Hoechst 33342, netropsin, and SN6999. The space group of the crystals from those complexes is P212121. However the crystal structure of the SN6999 complex is not isomorphous to that from the other three complexes. In all four refined crystal structures the drugs bind in the narrow minor groove at or close to the central AATT region of the dodecamer B-DNA duplex. The DNA conformation is influenced by the binding of drugs. The eight independent e6G:C base pairs have a conformation ranging from one with three-centered hydrogen bonds between the bases to a wobble conformation with two hydrogen bonds. The ethyl group of the eight e6G bases is mostly in the proximal orientation to N7. Our 1D and 2D-NMR studies of the same (free) dodecamer reveal that the e6G:C base pairs in the duplex are likely to adopt a wobble conformation in solution. Those results suggest that the e6G:C base pair has a dynamic equilibrium among various conformations, which may present an ambiguous signal to cells. In contrast, the e6G:T base pair adopts a Watson-Cricklike conformation. This may be a plausible explanation of why thymine is found preferentially incorporated across the e6G during replication.

Original languageEnglish (US)
Pages (from-to)18-44
Number of pages27
JournalAnnals of the New York Academy of Sciences
Volume726
StatePublished - 1994
Externally publishedYes

Fingerprint

Cytosine
Guanine
Polymorphism
Base Pairing
Conformations
Crystals
Pharmaceutical Preparations
Hydrogen
DNA
Netropsin
B-Form DNA
Ethylnitrosourea
Bisbenzimidazole
Nucleic Acid Conformation
Thymine
X Ray Crystallography
Hydrogen bonds
Alkylation
Crystal structure
Nuclear magnetic resonance

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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title = "Crystal and solution structures of d(CGC[e6G]AATTCGCG)-Drug complexes reveal conformational polymorphism of O6-Ethyl-Guanine: Cytosine base pair",
abstract = "O6-ethyl-guanine (e6G) is a relatively persistent alkylation lesion caused by the exposure of DNA to carcinogen N-ethyl-N-nitrosourea. We have studied the structural consequences of the e6G incorporation in DNA by X-ray crystallography and NMR. We have obtained crystals of the modified DNA dodecamer d(CGC[e6G]AATTCGCG) complexed to several minor groove binding drugs including Hoechst 33258, Hoechst 33342, netropsin, and SN6999. The space group of the crystals from those complexes is P212121. However the crystal structure of the SN6999 complex is not isomorphous to that from the other three complexes. In all four refined crystal structures the drugs bind in the narrow minor groove at or close to the central AATT region of the dodecamer B-DNA duplex. The DNA conformation is influenced by the binding of drugs. The eight independent e6G:C base pairs have a conformation ranging from one with three-centered hydrogen bonds between the bases to a wobble conformation with two hydrogen bonds. The ethyl group of the eight e6G bases is mostly in the proximal orientation to N7. Our 1D and 2D-NMR studies of the same (free) dodecamer reveal that the e6G:C base pairs in the duplex are likely to adopt a wobble conformation in solution. Those results suggest that the e6G:C base pair has a dynamic equilibrium among various conformations, which may present an ambiguous signal to cells. In contrast, the e6G:T base pair adopts a Watson-Cricklike conformation. This may be a plausible explanation of why thymine is found preferentially incorporated across the e6G during replication.",
author = "M. Sriram and Danzhou Yang and Gao, {Y. G.} and Wang, {A. H J}",
year = "1994",
language = "English (US)",
volume = "726",
pages = "18--44",
journal = "Annals of the New York Academy of Sciences",
issn = "0077-8923",
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TY - JOUR

T1 - Crystal and solution structures of d(CGC[e6G]AATTCGCG)-Drug complexes reveal conformational polymorphism of O6-Ethyl-Guanine

T2 - Cytosine base pair

AU - Sriram, M.

AU - Yang, Danzhou

AU - Gao, Y. G.

AU - Wang, A. H J

PY - 1994

Y1 - 1994

N2 - O6-ethyl-guanine (e6G) is a relatively persistent alkylation lesion caused by the exposure of DNA to carcinogen N-ethyl-N-nitrosourea. We have studied the structural consequences of the e6G incorporation in DNA by X-ray crystallography and NMR. We have obtained crystals of the modified DNA dodecamer d(CGC[e6G]AATTCGCG) complexed to several minor groove binding drugs including Hoechst 33258, Hoechst 33342, netropsin, and SN6999. The space group of the crystals from those complexes is P212121. However the crystal structure of the SN6999 complex is not isomorphous to that from the other three complexes. In all four refined crystal structures the drugs bind in the narrow minor groove at or close to the central AATT region of the dodecamer B-DNA duplex. The DNA conformation is influenced by the binding of drugs. The eight independent e6G:C base pairs have a conformation ranging from one with three-centered hydrogen bonds between the bases to a wobble conformation with two hydrogen bonds. The ethyl group of the eight e6G bases is mostly in the proximal orientation to N7. Our 1D and 2D-NMR studies of the same (free) dodecamer reveal that the e6G:C base pairs in the duplex are likely to adopt a wobble conformation in solution. Those results suggest that the e6G:C base pair has a dynamic equilibrium among various conformations, which may present an ambiguous signal to cells. In contrast, the e6G:T base pair adopts a Watson-Cricklike conformation. This may be a plausible explanation of why thymine is found preferentially incorporated across the e6G during replication.

AB - O6-ethyl-guanine (e6G) is a relatively persistent alkylation lesion caused by the exposure of DNA to carcinogen N-ethyl-N-nitrosourea. We have studied the structural consequences of the e6G incorporation in DNA by X-ray crystallography and NMR. We have obtained crystals of the modified DNA dodecamer d(CGC[e6G]AATTCGCG) complexed to several minor groove binding drugs including Hoechst 33258, Hoechst 33342, netropsin, and SN6999. The space group of the crystals from those complexes is P212121. However the crystal structure of the SN6999 complex is not isomorphous to that from the other three complexes. In all four refined crystal structures the drugs bind in the narrow minor groove at or close to the central AATT region of the dodecamer B-DNA duplex. The DNA conformation is influenced by the binding of drugs. The eight independent e6G:C base pairs have a conformation ranging from one with three-centered hydrogen bonds between the bases to a wobble conformation with two hydrogen bonds. The ethyl group of the eight e6G bases is mostly in the proximal orientation to N7. Our 1D and 2D-NMR studies of the same (free) dodecamer reveal that the e6G:C base pairs in the duplex are likely to adopt a wobble conformation in solution. Those results suggest that the e6G:C base pair has a dynamic equilibrium among various conformations, which may present an ambiguous signal to cells. In contrast, the e6G:T base pair adopts a Watson-Cricklike conformation. This may be a plausible explanation of why thymine is found preferentially incorporated across the e6G during replication.

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