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Recognition of O6-benzyl-2'-deoxyguanosine by a perimidinone-derived synthetic nucleoside: a DNA interstrand stacking interaction.

Kowal EA, Lad RR, Pallan PS, Dhummakupt E, Wawrzak Z, Egli M, Sturla SJ, Stone MP - Nucleic Acids Res. (2013)

Bottom Line: The structure of the modified Dickerson-Drew dodecamer (DDD) in which guanine at position G(4) has been replaced by O(6)-Bn-dG and cytosine C(9) has been replaced with dPer to form the modified O(6)-Bn-dG:dPer (DDD-XY) duplex [5'-d(C(1)G(2)C(3)X(4)A(5)A(6)T(7)T(8)Y(9)G(10)C(11)G(12))-3']2 (X = O(6)-Bn-dG, Y = dPer) reveals that dPer intercalates into the duplex and adopts the syn conformation about the glycosyl bond.This provides a binding pocket that allows the benzyl group of O(6)-Bn-dG to intercalate between Per and thymine of the 3'-neighbor A:T base pair.In contrast, the structure of the modified DDD in which cytosine at position C(9) is replaced with dPer to form the dG:dPer (DDD-GY) [5'-d(C(1)G(2)C(3)G(4)A(5)A(6)T(7)T(8)Y(9)G(10)C(11)G(12))-3']2 duplex (Y = dPer) reveals that dPer adopts the anti conformation about the glycosyl bond and forms a less stable wobble pairing interaction with guanine.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Center in Structural Biology, Vanderbilt University, Nashville, TN 37235, USA, Department of Health Sciences and Technology, Institute of Food, Nutrition and Health, ETH Zürich, CH-8092 Zürich, Switzerland, Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA and Department of Health Sciences and Technology, Synchrotron Research Center, Northwestern University, 9700 S Cass Ave, Argonne, IL 60439, USA.

ABSTRACT
The 2'-deoxynucleoside containing the synthetic base 1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-1H-perimidin-2(3H)-one] (dPer) recognizes in DNA the O(6)-benzyl-2'-deoxyguanosine nucleoside (O(6)-Bn-dG), formed by exposure to N-benzylmethylnitrosamine. Herein, we show how dPer distinguishes between O(6)-Bn-dG and dG in DNA. The structure of the modified Dickerson-Drew dodecamer (DDD) in which guanine at position G(4) has been replaced by O(6)-Bn-dG and cytosine C(9) has been replaced with dPer to form the modified O(6)-Bn-dG:dPer (DDD-XY) duplex [5'-d(C(1)G(2)C(3)X(4)A(5)A(6)T(7)T(8)Y(9)G(10)C(11)G(12))-3']2 (X = O(6)-Bn-dG, Y = dPer) reveals that dPer intercalates into the duplex and adopts the syn conformation about the glycosyl bond. This provides a binding pocket that allows the benzyl group of O(6)-Bn-dG to intercalate between Per and thymine of the 3'-neighbor A:T base pair. Nuclear magnetic resonance data suggest that a similar intercalative recognition mechanism applies in this sequence in solution. However, in solution, the benzyl ring of O(6)-Bn-dG undergoes rotation on the nuclear magnetic resonance time scale. In contrast, the structure of the modified DDD in which cytosine at position C(9) is replaced with dPer to form the dG:dPer (DDD-GY) [5'-d(C(1)G(2)C(3)G(4)A(5)A(6)T(7)T(8)Y(9)G(10)C(11)G(12))-3']2 duplex (Y = dPer) reveals that dPer adopts the anti conformation about the glycosyl bond and forms a less stable wobble pairing interaction with guanine.

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The average structure of the G4:Y9 base pair, in the DDD-GY duplex. G4 forms a wobble pair with the complementary dPer (Y9) base. The anticipated hydrogen bonds are indicated as gray dashed lines.
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gkt488-F9: The average structure of the G4:Y9 base pair, in the DDD-GY duplex. G4 forms a wobble pair with the complementary dPer (Y9) base. The anticipated hydrogen bonds are indicated as gray dashed lines.

Mentions: The structure of the dG:dPer (DDD-GY) duplex was determined using a simulated annealing rMD protocol, restrained by experimental distance restraints determined from NOEs. Supplementary Table S4 shows the restraints used for rMD calculations. Nine structures were energy minimized and superimposed to obtain the average structure (Supplementary Figure S9). Supplementary Figure S10 shows these superimposed structures and the average structure. The latter was in good agreement with the experimental restraints confirmed by CORMA (52) analysis. Supplementary Table S5 shows the structural statistics. Figure 8 shows the DDD-GY duplex in the region of the C3:G10, G4:Y9 and A5:T8 base pairs. The dPer Y9 base formed a wobble base pair with the complementary guanine G4, involving two hydrogen bonds (Figure 9), which was supported by a strong cross-peak between imino protons of G4 and Y9 of opposite strands (cross-peak u, Figure 5b). The dPer ring was oriented in the major groove and adopted the anti conformation about the glycosyl bond. It did not disrupt neighbor base pairs. The dPer base stacked with its 5′ neighbor T8, but it did not stack well with its 3′ neighbor G10 (Figure 10). The complementary guanine, G4 stacked well with its 3′ neighbor A5, but not with C3. Helicoidal analysis (Supplementary Figures S11, S12, S13 and S14) revealed that the ζ angle of the dPer nucleotide increased by ∼50° compared with the unmodified duplex, which corroborated the reduced stacking between dPer (Y9) and the 3′ neighbor guanine (G10) (Supplementary Figure S14).Figure 8.


Recognition of O6-benzyl-2'-deoxyguanosine by a perimidinone-derived synthetic nucleoside: a DNA interstrand stacking interaction.

Kowal EA, Lad RR, Pallan PS, Dhummakupt E, Wawrzak Z, Egli M, Sturla SJ, Stone MP - Nucleic Acids Res. (2013)

The average structure of the G4:Y9 base pair, in the DDD-GY duplex. G4 forms a wobble pair with the complementary dPer (Y9) base. The anticipated hydrogen bonds are indicated as gray dashed lines.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3753623&req=5

gkt488-F9: The average structure of the G4:Y9 base pair, in the DDD-GY duplex. G4 forms a wobble pair with the complementary dPer (Y9) base. The anticipated hydrogen bonds are indicated as gray dashed lines.
Mentions: The structure of the dG:dPer (DDD-GY) duplex was determined using a simulated annealing rMD protocol, restrained by experimental distance restraints determined from NOEs. Supplementary Table S4 shows the restraints used for rMD calculations. Nine structures were energy minimized and superimposed to obtain the average structure (Supplementary Figure S9). Supplementary Figure S10 shows these superimposed structures and the average structure. The latter was in good agreement with the experimental restraints confirmed by CORMA (52) analysis. Supplementary Table S5 shows the structural statistics. Figure 8 shows the DDD-GY duplex in the region of the C3:G10, G4:Y9 and A5:T8 base pairs. The dPer Y9 base formed a wobble base pair with the complementary guanine G4, involving two hydrogen bonds (Figure 9), which was supported by a strong cross-peak between imino protons of G4 and Y9 of opposite strands (cross-peak u, Figure 5b). The dPer ring was oriented in the major groove and adopted the anti conformation about the glycosyl bond. It did not disrupt neighbor base pairs. The dPer base stacked with its 5′ neighbor T8, but it did not stack well with its 3′ neighbor G10 (Figure 10). The complementary guanine, G4 stacked well with its 3′ neighbor A5, but not with C3. Helicoidal analysis (Supplementary Figures S11, S12, S13 and S14) revealed that the ζ angle of the dPer nucleotide increased by ∼50° compared with the unmodified duplex, which corroborated the reduced stacking between dPer (Y9) and the 3′ neighbor guanine (G10) (Supplementary Figure S14).Figure 8.

Bottom Line: The structure of the modified Dickerson-Drew dodecamer (DDD) in which guanine at position G(4) has been replaced by O(6)-Bn-dG and cytosine C(9) has been replaced with dPer to form the modified O(6)-Bn-dG:dPer (DDD-XY) duplex [5'-d(C(1)G(2)C(3)X(4)A(5)A(6)T(7)T(8)Y(9)G(10)C(11)G(12))-3']2 (X = O(6)-Bn-dG, Y = dPer) reveals that dPer intercalates into the duplex and adopts the syn conformation about the glycosyl bond.This provides a binding pocket that allows the benzyl group of O(6)-Bn-dG to intercalate between Per and thymine of the 3'-neighbor A:T base pair.In contrast, the structure of the modified DDD in which cytosine at position C(9) is replaced with dPer to form the dG:dPer (DDD-GY) [5'-d(C(1)G(2)C(3)G(4)A(5)A(6)T(7)T(8)Y(9)G(10)C(11)G(12))-3']2 duplex (Y = dPer) reveals that dPer adopts the anti conformation about the glycosyl bond and forms a less stable wobble pairing interaction with guanine.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Center in Structural Biology, Vanderbilt University, Nashville, TN 37235, USA, Department of Health Sciences and Technology, Institute of Food, Nutrition and Health, ETH Zürich, CH-8092 Zürich, Switzerland, Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA and Department of Health Sciences and Technology, Synchrotron Research Center, Northwestern University, 9700 S Cass Ave, Argonne, IL 60439, USA.

ABSTRACT
The 2'-deoxynucleoside containing the synthetic base 1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-1H-perimidin-2(3H)-one] (dPer) recognizes in DNA the O(6)-benzyl-2'-deoxyguanosine nucleoside (O(6)-Bn-dG), formed by exposure to N-benzylmethylnitrosamine. Herein, we show how dPer distinguishes between O(6)-Bn-dG and dG in DNA. The structure of the modified Dickerson-Drew dodecamer (DDD) in which guanine at position G(4) has been replaced by O(6)-Bn-dG and cytosine C(9) has been replaced with dPer to form the modified O(6)-Bn-dG:dPer (DDD-XY) duplex [5'-d(C(1)G(2)C(3)X(4)A(5)A(6)T(7)T(8)Y(9)G(10)C(11)G(12))-3']2 (X = O(6)-Bn-dG, Y = dPer) reveals that dPer intercalates into the duplex and adopts the syn conformation about the glycosyl bond. This provides a binding pocket that allows the benzyl group of O(6)-Bn-dG to intercalate between Per and thymine of the 3'-neighbor A:T base pair. Nuclear magnetic resonance data suggest that a similar intercalative recognition mechanism applies in this sequence in solution. However, in solution, the benzyl ring of O(6)-Bn-dG undergoes rotation on the nuclear magnetic resonance time scale. In contrast, the structure of the modified DDD in which cytosine at position C(9) is replaced with dPer to form the dG:dPer (DDD-GY) [5'-d(C(1)G(2)C(3)G(4)A(5)A(6)T(7)T(8)Y(9)G(10)C(11)G(12))-3']2 duplex (Y = dPer) reveals that dPer adopts the anti conformation about the glycosyl bond and forms a less stable wobble pairing interaction with guanine.

Show MeSH
Related in: MedlinePlus