Multiple conformations of an intercalated (-)-(7S, 8R, 9S, 10R)-N6- [10-(7,8,9,10-tetrahydrobenzo[a]pyrenyl)]-2'-deoxyadenosyl adduct in the N- ras codon 61 sequence

Irene S. Zegar, Parvathi Chary, Ritche J. Jabil, Pamela J. Tamura, Tommy N. Johansen, Robert (Stephen) Lloyd, Constance M. Harris, Thomas M. Harris, Michael P. Stone

Research output: Contribution to journalArticle

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Abstract

The structure of the (-)-(7S,8R,9S,10R)-N6-[10-(7,8,9,10- tetrahydrobenzo[a]pyrenyl)]-2'-deoxyadenosyl adduct at A7 of 5'- d(CGGACAAGAAG)-3·5'-d(CTTCTTGTCCG)-3', derived from trans addition of the exocyclic N6-amino group of dA to (-)-(7S,8R,9R,10S)-7,8-dihydroxy-9,10- epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(-)-DE2], was determined using molecular dynamics simulations restrained by 532 NOEs from 1H NMR. This was named the SRSR(61,3) adduct, derived from the N-ras protooncogene at and adjacent to the nucleotides encoding amino acid 61 (underlined) of the p21 gene product. The solution structure of this adduct was best described as a mixture of two conformations in rapid equilibrium on the NMR time scale. The two populations differed in the pseudorotation angle of the sugar ring for the 5'-neighboring base A6, as determined from scalar coupling data. One population, estimated to be present at 53%, had the A6 deoxyribose in the C2'-endo conformation, while in the second conformation the A6 deoxyribose was in the C3'-endo conformation. NOEs between C5, A6, and (SRSR)A7 were either disrupted or weakened, as were those in the complementary strand between C15, T16, and T17. Major groove NOEs were observed between the benzo[a]pyrene aromatic protons, H1, H2, H3, H4, H5, and H6, and T16 CH3. Minor groove NOEs were observed between H1, H2, and H3 of benzo[a]pyrene and T16 HI' and H2' and T17 HI' and H2'. The benzo[a]pyrene protons H10, H11, and H12 showed NOEs to A6 H1', H2', and H2. The chemical shifts of the pyrenyl moiety were dispersed over a 1.9 ppm range. Upfield chemical shifts of 2.4 ppm for T16 N3H, 1.1 ppm for T17 N3H, 1.3 and 1.0 ppm for T16 H6 and CH3, 0.85 ppm for T16 HI', and 0.80 and 0.90 ppm for C15 H2' and H2'' were observed. These observations were consistent with intercalation of the pyrenyl moiety toward the 5' direction of (SRSR)A7. The results were compared to the isomeric SRSR(61,2) adduct [I. S. Zegar, S. J. Kim, T. N. Johansen, P. J. Horton, C. M. Harris, T. M. Harris, and M.P. Stone (1996) Biochemistry 35, 6212-6224] and revealed the role of DNA sequence in modulating the conformation of this benzo[a]pyrene adduct.

Original languageEnglish (US)
Pages (from-to)16516-16528
Number of pages13
JournalBiochemistry
Volume37
Issue number47
DOIs
StatePublished - Nov 24 1998
Externally publishedYes

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Benzo(a)pyrene
Codon
Conformations
Deoxyribose
Protons
Chemical shift
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
Nuclear magnetic resonance
Molecular Dynamics Simulation
Biochemistry
Population
DNA sequences
Intercalation
Nucleotides
Sugars
Molecular dynamics
Amino Acids
Genes
Computer simulation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Multiple conformations of an intercalated (-)-(7S, 8R, 9S, 10R)-N6- [10-(7,8,9,10-tetrahydrobenzo[a]pyrenyl)]-2'-deoxyadenosyl adduct in the N- ras codon 61 sequence. / Zegar, Irene S.; Chary, Parvathi; Jabil, Ritche J.; Tamura, Pamela J.; Johansen, Tommy N.; Lloyd, Robert (Stephen); Harris, Constance M.; Harris, Thomas M.; Stone, Michael P.

In: Biochemistry, Vol. 37, No. 47, 24.11.1998, p. 16516-16528.

Research output: Contribution to journalArticle

Zegar, Irene S. ; Chary, Parvathi ; Jabil, Ritche J. ; Tamura, Pamela J. ; Johansen, Tommy N. ; Lloyd, Robert (Stephen) ; Harris, Constance M. ; Harris, Thomas M. ; Stone, Michael P. / Multiple conformations of an intercalated (-)-(7S, 8R, 9S, 10R)-N6- [10-(7,8,9,10-tetrahydrobenzo[a]pyrenyl)]-2'-deoxyadenosyl adduct in the N- ras codon 61 sequence. In: Biochemistry. 1998 ; Vol. 37, No. 47. pp. 16516-16528.
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title = "Multiple conformations of an intercalated (-)-(7S, 8R, 9S, 10R)-N6- [10-(7,8,9,10-tetrahydrobenzo[a]pyrenyl)]-2'-deoxyadenosyl adduct in the N- ras codon 61 sequence",
abstract = "The structure of the (-)-(7S,8R,9S,10R)-N6-[10-(7,8,9,10- tetrahydrobenzo[a]pyrenyl)]-2'-deoxyadenosyl adduct at A7 of 5'- d(CGGACAAGAAG)-3·5'-d(CTTCTTGTCCG)-3', derived from trans addition of the exocyclic N6-amino group of dA to (-)-(7S,8R,9R,10S)-7,8-dihydroxy-9,10- epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(-)-DE2], was determined using molecular dynamics simulations restrained by 532 NOEs from 1H NMR. This was named the SRSR(61,3) adduct, derived from the N-ras protooncogene at and adjacent to the nucleotides encoding amino acid 61 (underlined) of the p21 gene product. The solution structure of this adduct was best described as a mixture of two conformations in rapid equilibrium on the NMR time scale. The two populations differed in the pseudorotation angle of the sugar ring for the 5'-neighboring base A6, as determined from scalar coupling data. One population, estimated to be present at 53{\%}, had the A6 deoxyribose in the C2'-endo conformation, while in the second conformation the A6 deoxyribose was in the C3'-endo conformation. NOEs between C5, A6, and (SRSR)A7 were either disrupted or weakened, as were those in the complementary strand between C15, T16, and T17. Major groove NOEs were observed between the benzo[a]pyrene aromatic protons, H1, H2, H3, H4, H5, and H6, and T16 CH3. Minor groove NOEs were observed between H1, H2, and H3 of benzo[a]pyrene and T16 HI' and H2' and T17 HI' and H2'. The benzo[a]pyrene protons H10, H11, and H12 showed NOEs to A6 H1', H2', and H2. The chemical shifts of the pyrenyl moiety were dispersed over a 1.9 ppm range. Upfield chemical shifts of 2.4 ppm for T16 N3H, 1.1 ppm for T17 N3H, 1.3 and 1.0 ppm for T16 H6 and CH3, 0.85 ppm for T16 HI', and 0.80 and 0.90 ppm for C15 H2' and H2'' were observed. These observations were consistent with intercalation of the pyrenyl moiety toward the 5' direction of (SRSR)A7. The results were compared to the isomeric SRSR(61,2) adduct [I. S. Zegar, S. J. Kim, T. N. Johansen, P. J. Horton, C. M. Harris, T. M. Harris, and M.P. Stone (1996) Biochemistry 35, 6212-6224] and revealed the role of DNA sequence in modulating the conformation of this benzo[a]pyrene adduct.",
author = "Zegar, {Irene S.} and Parvathi Chary and Jabil, {Ritche J.} and Tamura, {Pamela J.} and Johansen, {Tommy N.} and Lloyd, {Robert (Stephen)} and Harris, {Constance M.} and Harris, {Thomas M.} and Stone, {Michael P.}",
year = "1998",
month = "11",
day = "24",
doi = "10.1021/bi9817616",
language = "English (US)",
volume = "37",
pages = "16516--16528",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "47",

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TY - JOUR

T1 - Multiple conformations of an intercalated (-)-(7S, 8R, 9S, 10R)-N6- [10-(7,8,9,10-tetrahydrobenzo[a]pyrenyl)]-2'-deoxyadenosyl adduct in the N- ras codon 61 sequence

AU - Zegar, Irene S.

AU - Chary, Parvathi

AU - Jabil, Ritche J.

AU - Tamura, Pamela J.

AU - Johansen, Tommy N.

AU - Lloyd, Robert (Stephen)

AU - Harris, Constance M.

AU - Harris, Thomas M.

AU - Stone, Michael P.

PY - 1998/11/24

Y1 - 1998/11/24

N2 - The structure of the (-)-(7S,8R,9S,10R)-N6-[10-(7,8,9,10- tetrahydrobenzo[a]pyrenyl)]-2'-deoxyadenosyl adduct at A7 of 5'- d(CGGACAAGAAG)-3·5'-d(CTTCTTGTCCG)-3', derived from trans addition of the exocyclic N6-amino group of dA to (-)-(7S,8R,9R,10S)-7,8-dihydroxy-9,10- epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(-)-DE2], was determined using molecular dynamics simulations restrained by 532 NOEs from 1H NMR. This was named the SRSR(61,3) adduct, derived from the N-ras protooncogene at and adjacent to the nucleotides encoding amino acid 61 (underlined) of the p21 gene product. The solution structure of this adduct was best described as a mixture of two conformations in rapid equilibrium on the NMR time scale. The two populations differed in the pseudorotation angle of the sugar ring for the 5'-neighboring base A6, as determined from scalar coupling data. One population, estimated to be present at 53%, had the A6 deoxyribose in the C2'-endo conformation, while in the second conformation the A6 deoxyribose was in the C3'-endo conformation. NOEs between C5, A6, and (SRSR)A7 were either disrupted or weakened, as were those in the complementary strand between C15, T16, and T17. Major groove NOEs were observed between the benzo[a]pyrene aromatic protons, H1, H2, H3, H4, H5, and H6, and T16 CH3. Minor groove NOEs were observed between H1, H2, and H3 of benzo[a]pyrene and T16 HI' and H2' and T17 HI' and H2'. The benzo[a]pyrene protons H10, H11, and H12 showed NOEs to A6 H1', H2', and H2. The chemical shifts of the pyrenyl moiety were dispersed over a 1.9 ppm range. Upfield chemical shifts of 2.4 ppm for T16 N3H, 1.1 ppm for T17 N3H, 1.3 and 1.0 ppm for T16 H6 and CH3, 0.85 ppm for T16 HI', and 0.80 and 0.90 ppm for C15 H2' and H2'' were observed. These observations were consistent with intercalation of the pyrenyl moiety toward the 5' direction of (SRSR)A7. The results were compared to the isomeric SRSR(61,2) adduct [I. S. Zegar, S. J. Kim, T. N. Johansen, P. J. Horton, C. M. Harris, T. M. Harris, and M.P. Stone (1996) Biochemistry 35, 6212-6224] and revealed the role of DNA sequence in modulating the conformation of this benzo[a]pyrene adduct.

AB - The structure of the (-)-(7S,8R,9S,10R)-N6-[10-(7,8,9,10- tetrahydrobenzo[a]pyrenyl)]-2'-deoxyadenosyl adduct at A7 of 5'- d(CGGACAAGAAG)-3·5'-d(CTTCTTGTCCG)-3', derived from trans addition of the exocyclic N6-amino group of dA to (-)-(7S,8R,9R,10S)-7,8-dihydroxy-9,10- epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(-)-DE2], was determined using molecular dynamics simulations restrained by 532 NOEs from 1H NMR. This was named the SRSR(61,3) adduct, derived from the N-ras protooncogene at and adjacent to the nucleotides encoding amino acid 61 (underlined) of the p21 gene product. The solution structure of this adduct was best described as a mixture of two conformations in rapid equilibrium on the NMR time scale. The two populations differed in the pseudorotation angle of the sugar ring for the 5'-neighboring base A6, as determined from scalar coupling data. One population, estimated to be present at 53%, had the A6 deoxyribose in the C2'-endo conformation, while in the second conformation the A6 deoxyribose was in the C3'-endo conformation. NOEs between C5, A6, and (SRSR)A7 were either disrupted or weakened, as were those in the complementary strand between C15, T16, and T17. Major groove NOEs were observed between the benzo[a]pyrene aromatic protons, H1, H2, H3, H4, H5, and H6, and T16 CH3. Minor groove NOEs were observed between H1, H2, and H3 of benzo[a]pyrene and T16 HI' and H2' and T17 HI' and H2'. The benzo[a]pyrene protons H10, H11, and H12 showed NOEs to A6 H1', H2', and H2. The chemical shifts of the pyrenyl moiety were dispersed over a 1.9 ppm range. Upfield chemical shifts of 2.4 ppm for T16 N3H, 1.1 ppm for T17 N3H, 1.3 and 1.0 ppm for T16 H6 and CH3, 0.85 ppm for T16 HI', and 0.80 and 0.90 ppm for C15 H2' and H2'' were observed. These observations were consistent with intercalation of the pyrenyl moiety toward the 5' direction of (SRSR)A7. The results were compared to the isomeric SRSR(61,2) adduct [I. S. Zegar, S. J. Kim, T. N. Johansen, P. J. Horton, C. M. Harris, T. M. Harris, and M.P. Stone (1996) Biochemistry 35, 6212-6224] and revealed the role of DNA sequence in modulating the conformation of this benzo[a]pyrene adduct.

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