Conformation of B-DNA containing O6-ethyl-G-C base pairs stabilized by minor groove binding drugs: Molecular structure of d(CGC[e6G]AATTCGCG complexed with Hoechst 33258 or Hoechst 33342

M. Sriram, G. A. Van der Marel, H. L.P.F. Roelen, J. H. Van Boom, A. H.J. Wang

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101 引文 斯高帕斯(Scopus)

摘要

O6-ethyl-G (e6G) is an important DNA lesion, caused by the exposure of cells to alkylating agents such as N-ethyl-N-nitrosourea. A strong correlation exists between persistence of e6G lesion and subsequent carcinogenic conversion. We have determined the three-dimensional structure of a DNA molecule incorporating the e6G lesion by X-ray crystallography. The DNA dodecamer d(CGC[e6G]AATTCGCG), complexed to minor groove binding drugs Hoechst 33258 or Hoechst 33342, has been crystallized in the space group P212121, isomorphous to other related dodecamer DNA crystals. In addition, the native dodecamer d(CGCGMTTCGCG) was crystallized with Hoechst 33342. All three new structures were solved by the molecular replacement method and refined by the constrained least squares procedure to R-factors of ~16% at ~2.0 Å resolution. In the structure of three Hoechst drug-dodecamer complexes in addition to the one published earlier [Teng et al. (1988) Nucleic Acids Res., 16, 2671-2690], the Hoechst molecule lies squarely at the central AATT site with the ends approaching the G4-C21 and the G16-C9 base pairs, consistent with other spectroscopic data, but not with another crystal structure reported [Pjura et al. (1987) J. Mol. Biol., 197, 257-271]. The two independent e6G-C base pairs in the DNA duplex adopt different base pairing schemes. The e6G4-C21 base pair has a configuration similar to a normal Watson-Crick base pair, except with bifurcated hydrogen bonds between e6G4 and C21, and the ethyl group is in the proximal orientation. In contrast, the e6G16-C9 base pair adopts a wobble configuration and the ethyl group is in the distal orientation. There may be a dynamic equilibrium between these two configurations for the e6G-C base pair, which presents an ambiguous signal to the cellular replication and repair mechanisms. In contrast, thymine can pair with e6G in only one way, albeit imperfect, mimicking a Watson-Crick base pair. This may be a plausible explanation of why thymine is found preferentially incorporated across the e6G during replication.

原文英語
頁(從 - 到)225-232
頁數8
期刊EMBO Journal
11
發行號1
DOIs
出版狀態已發佈 - 1992
對外發佈

ASJC Scopus subject areas

  • 神經科學 (全部)
  • 分子生物學
  • 生物化學、遺傳與分子生物學 (全部)
  • 免疫學與微生物學 (全部)

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