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

DOI Web Site 被引用文献13件
  • Hiroshi Sugiyama
    Department of Synthetic Chemistry and Biological Chemistry, Faculty of Engineering, Kyoto University, Kyoto 606-01, Japan; and Department of Cell and Structural Biology and Department of Chemistry, University of Illinois at Urbana–Champaign, Urbana, IL 61801
  • Chenyang Lian
    Department of Synthetic Chemistry and Biological Chemistry, Faculty of Engineering, Kyoto University, Kyoto 606-01, Japan; and Department of Cell and Structural Biology and Department of Chemistry, University of Illinois at Urbana–Champaign, Urbana, IL 61801
  • Mariko Isomura
    Department of Synthetic Chemistry and Biological Chemistry, Faculty of Engineering, Kyoto University, Kyoto 606-01, Japan; and Department of Cell and Structural Biology and Department of Chemistry, University of Illinois at Urbana–Champaign, Urbana, IL 61801
  • Isao Saito
    Department of Synthetic Chemistry and Biological Chemistry, Faculty of Engineering, Kyoto University, Kyoto 606-01, Japan; and Department of Cell and Structural Biology and Department of Chemistry, University of Illinois at Urbana–Champaign, Urbana, IL 61801
  • Andrew H.-J. Wang
    Department of Synthetic Chemistry and Biological Chemistry, Faculty of Engineering, Kyoto University, Kyoto 606-01, Japan; and Department of Cell and Structural Biology and Department of Chemistry, University of Illinois at Urbana–Champaign, Urbana, IL 61801

抄録

<jats:p>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.</jats:p>

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