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

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

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)14405-14410
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number25
DOIs
Publication statusPublished - Dec 10 1996
Externally publishedYes

ASJC Scopus subject areas

  • General

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