Structure and Isomerization of an Intrastrand Cisplatin-Cross-Linked Octamer DNA Duplex by NMR Analysis

Danzhou Yang, Stella S.G.E. van Boom, Jan Reedijk, Jacques H. van Boom, Andrew H.J. Wang

Research output: Contribution to journalArticle

219 Scopus citations

Abstract

The anticancer platinum compound cis-Pt(NH3)2Cl2 (cisplatin) forms covalent cross-linked adducts with DNA, with the intrastrand didentate adduct between two adjacent guanines being the major product. The platinum atom is coordinated at the N7 positions of adjacent guanines. The duplex consisting of d(CCTG*G*TCC) and its complement d(GGACCAGG), where G*G* stands for the cisplatin crosslinked lesion site, has been analyzed by ID- and 2D-NMR spectroscopy and its structure solved by the NOE-restrained refinement procedure with the aim to understand the structural distortion associated with the lesion. The refined duplex is unwound (~-21°) and kinked (~58°) toward the major groove at the G*G* site, and the minor groove is significantly widened. The deoxyriboses of the G4* and G5* nucleotides are of the N-type (C3'-endo) and S-type (C2'-endo) conformations, respectively. The two guanine bases adopt the R-configuration (the α/β angles being 112°/290°, respectively), such that the Gs*H8 proton (upfield at 8.19 ppm) senses the ring current shielding effect of the G4* base (G4*H8 at 8.76 ppm). The G4*.C13 base pair is perturbed significantly, consistent with the lack of detection of its imino proton. The intrastrand Pt-G*pG* cross-link is metastable in the present DNA duplex. The molecule is slowly converted into a more stable /referstrand didentate adduct (between G4 and G9) promoted by the presence of the nucleophilic chloride ion. The reason why the Pt-N7(3'-G*) bond can be ruptured and a new Pt-N7 bond formed may be due to the fact that the more flexible 5'-G*.C base pair at the didentate lesion site is able to absorb the strain better, but the more rigid 3'-G*.C base pair cannot and results in substitution. The biological implications of this structural isomerization are discussed.

Original languageEnglish (US)
Pages (from-to)12912-12920
Number of pages9
JournalBiochemistry
Volume34
Issue number39
DOIs
StatePublished - Oct 1995

ASJC Scopus subject areas

  • Biochemistry

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