Distamycin A modulates the sequence specificity of DNA alkylation by duocarmycin A

Hiroshi Sugiyama, Chenyang Lian, Mariko Isomura, Isao Saito, Andrew H.J. Wang

研究成果: 雜誌貢獻文章同行評審

57 引文 斯高帕斯(Scopus)


Duocarmycin A (Duo) normally alkylates adenine N3 at the 3' end of A+T- rich sequences in DNA. The efficient adenine alkylation by Duo is achieved by its monomeric binding to the DNA minor groove. The addition of another minor groove binder, distamycin A (Dist), dramatically modulates the site of DNA alkylation by Duo, and the alkylation switches preferentially to G residues in G+C-rich sequences. HPLC product analysis using oligonucleotides revealed a highly efficient G-N3 alkylation via the cooperative binding of a heterodimer between Duo and Dist to the minor groove. The three-dimensional structure of the ternary alkylated complex of Duo/Dist/d(CAGGTGGT)- d(ACCACCTG) has been determined by nuclear Overhauser effect (NOE)-restrained refinement using 750 MHz two-dimensional NOE spectroscopy data. The refined NMR structure fully explains the sequence requirement of such modulated alkylations. This is the first demonstration of Duo DNA alkylation through cooperative binding with another structurally different natural product, and it suggests a promising new way to alter or modify the DNA alkylation selectivity in a predictable manner.

頁(從 - 到)14405-14410
期刊Proceedings of the National Academy of Sciences of the United States of America
出版狀態已發佈 - 12月 10 1996

ASJC Scopus subject areas

  • 多學科


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