Solution structure of a DNA duplex containing mispair-aligned N4C-ethyl-N4C interstrand cross-linked cytosines

Mateus Webba Da Silva, Anne M. Noronha, David M. Noll, Paul S. Miller, O. Michael Colvin, Michael P. Gamcsik

Research output: Contribution to journalArticle

Abstract

The solution structure of an interstrand cross-linked self-complementary oligodeoxynucleotide containing directly opposed alkylated N4C-ethyl-N4C cytosine bases was determined by molecular dynamics calculations guided by NMR-derived restraints. The undecamer d(CGAAAC*TTTCG)2, where C* represents directly opposed alkylated N4C-ethyl-N4C cytosine bases, serves as model for the cytotoxic cross-links formed by bifunctional alkylating agents used in cancer therapy. The structure of the duplex shows the cross-link protruding into the major groove. An increase in the diameter of the DNA at the pseudoplatform formed by the cross-linked residues creates an A-DNA characteristic hole in the central portion of the DNA. This results in a centrally underwound base step and a number of subsequent overwinding steps leading to an overall axis bend toward the major groove. The structure shows narrowing of both minor and major grooves in the proximity of the cross-link. The perturbation leads to preferential intrastrand base stacking, disruption of adjacent canonical (A·T) base pairing, and buckling of base pairs, the extent of which diminishes with progression away from the lesion site. Overall, the distortion induced by the cross-link spreads over three base pairs on the 5′- and 3′-sides of the cross-link.

Original languageEnglish (US)
Pages (from-to)15181-15188
Number of pages8
JournalBiochemistry®
Volume41
Issue number51
DOIs
StatePublished - Dec 24 2002

Fingerprint

Cytosine
Base Pairing
A-Form DNA
Oligodeoxyribonucleotides
Alkylating Agents
DNA
Buckling
Molecular dynamics
Nuclear magnetic resonance
Molecular Dynamics Simulation
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Biochemistry

Cite this

Da Silva, M. W., Noronha, A. M., Noll, D. M., Miller, P. S., Colvin, O. M., & Gamcsik, M. P. (2002). Solution structure of a DNA duplex containing mispair-aligned N4C-ethyl-N4C interstrand cross-linked cytosines. Biochemistry®, 41(51), 15181-15188. https://doi.org/10.1021/bi026368l

Solution structure of a DNA duplex containing mispair-aligned N4C-ethyl-N4C interstrand cross-linked cytosines. / Da Silva, Mateus Webba; Noronha, Anne M.; Noll, David M.; Miller, Paul S.; Colvin, O. Michael; Gamcsik, Michael P.

In: Biochemistry®, Vol. 41, No. 51, 24.12.2002, p. 15181-15188.

Research output: Contribution to journalArticle

Da Silva, MW, Noronha, AM, Noll, DM, Miller, PS, Colvin, OM & Gamcsik, MP 2002, 'Solution structure of a DNA duplex containing mispair-aligned N4C-ethyl-N4C interstrand cross-linked cytosines', Biochemistry®, vol. 41, no. 51, pp. 15181-15188. https://doi.org/10.1021/bi026368l
Da Silva, Mateus Webba ; Noronha, Anne M. ; Noll, David M. ; Miller, Paul S. ; Colvin, O. Michael ; Gamcsik, Michael P. / Solution structure of a DNA duplex containing mispair-aligned N4C-ethyl-N4C interstrand cross-linked cytosines. In: Biochemistry®. 2002 ; Vol. 41, No. 51. pp. 15181-15188.
@article{8f9d461462db478a8ae22de7ece055f1,
title = "Solution structure of a DNA duplex containing mispair-aligned N4C-ethyl-N4C interstrand cross-linked cytosines",
abstract = "The solution structure of an interstrand cross-linked self-complementary oligodeoxynucleotide containing directly opposed alkylated N4C-ethyl-N4C cytosine bases was determined by molecular dynamics calculations guided by NMR-derived restraints. The undecamer d(CGAAAC*TTTCG)2, where C* represents directly opposed alkylated N4C-ethyl-N4C cytosine bases, serves as model for the cytotoxic cross-links formed by bifunctional alkylating agents used in cancer therapy. The structure of the duplex shows the cross-link protruding into the major groove. An increase in the diameter of the DNA at the pseudoplatform formed by the cross-linked residues creates an A-DNA characteristic hole in the central portion of the DNA. This results in a centrally underwound base step and a number of subsequent overwinding steps leading to an overall axis bend toward the major groove. The structure shows narrowing of both minor and major grooves in the proximity of the cross-link. The perturbation leads to preferential intrastrand base stacking, disruption of adjacent canonical (A·T) base pairing, and buckling of base pairs, the extent of which diminishes with progression away from the lesion site. Overall, the distortion induced by the cross-link spreads over three base pairs on the 5′- and 3′-sides of the cross-link.",
author = "{Da Silva}, {Mateus Webba} and Noronha, {Anne M.} and Noll, {David M.} and Miller, {Paul S.} and Colvin, {O. Michael} and Gamcsik, {Michael P.}",
year = "2002",
month = "12",
day = "24",
doi = "10.1021/bi026368l",
language = "English (US)",
volume = "41",
pages = "15181--15188",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "51",

}

TY - JOUR

T1 - Solution structure of a DNA duplex containing mispair-aligned N4C-ethyl-N4C interstrand cross-linked cytosines

AU - Da Silva, Mateus Webba

AU - Noronha, Anne M.

AU - Noll, David M.

AU - Miller, Paul S.

AU - Colvin, O. Michael

AU - Gamcsik, Michael P.

PY - 2002/12/24

Y1 - 2002/12/24

N2 - The solution structure of an interstrand cross-linked self-complementary oligodeoxynucleotide containing directly opposed alkylated N4C-ethyl-N4C cytosine bases was determined by molecular dynamics calculations guided by NMR-derived restraints. The undecamer d(CGAAAC*TTTCG)2, where C* represents directly opposed alkylated N4C-ethyl-N4C cytosine bases, serves as model for the cytotoxic cross-links formed by bifunctional alkylating agents used in cancer therapy. The structure of the duplex shows the cross-link protruding into the major groove. An increase in the diameter of the DNA at the pseudoplatform formed by the cross-linked residues creates an A-DNA characteristic hole in the central portion of the DNA. This results in a centrally underwound base step and a number of subsequent overwinding steps leading to an overall axis bend toward the major groove. The structure shows narrowing of both minor and major grooves in the proximity of the cross-link. The perturbation leads to preferential intrastrand base stacking, disruption of adjacent canonical (A·T) base pairing, and buckling of base pairs, the extent of which diminishes with progression away from the lesion site. Overall, the distortion induced by the cross-link spreads over three base pairs on the 5′- and 3′-sides of the cross-link.

AB - The solution structure of an interstrand cross-linked self-complementary oligodeoxynucleotide containing directly opposed alkylated N4C-ethyl-N4C cytosine bases was determined by molecular dynamics calculations guided by NMR-derived restraints. The undecamer d(CGAAAC*TTTCG)2, where C* represents directly opposed alkylated N4C-ethyl-N4C cytosine bases, serves as model for the cytotoxic cross-links formed by bifunctional alkylating agents used in cancer therapy. The structure of the duplex shows the cross-link protruding into the major groove. An increase in the diameter of the DNA at the pseudoplatform formed by the cross-linked residues creates an A-DNA characteristic hole in the central portion of the DNA. This results in a centrally underwound base step and a number of subsequent overwinding steps leading to an overall axis bend toward the major groove. The structure shows narrowing of both minor and major grooves in the proximity of the cross-link. The perturbation leads to preferential intrastrand base stacking, disruption of adjacent canonical (A·T) base pairing, and buckling of base pairs, the extent of which diminishes with progression away from the lesion site. Overall, the distortion induced by the cross-link spreads over three base pairs on the 5′- and 3′-sides of the cross-link.

UR - http://www.scopus.com/inward/record.url?scp=0347928863&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0347928863&partnerID=8YFLogxK

U2 - 10.1021/bi026368l

DO - 10.1021/bi026368l

M3 - Article

C2 - 12484755

AN - SCOPUS:0347928863

VL - 41

SP - 15181

EP - 15188

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 51

ER -