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Molecular Mechanisms for the Sequence Recognition of DNA by (+)-CC-1065

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Molecular Aspects of Chemotherapy

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Abstract

(+)-CC-1065 is an extremely potent antitumor antibiotic produced by Streptomyces zelensis We have previously postulated that a sequence dependent catalytic activation and/or conformational flexibility are/is responsible for the DNA sequence selectivity of (+)-CC-1065. In this review article we demonstrated that both of these factors are likely to be involved. Using a 12-mer DNA duplex containing a unique (+)-CC-1065 bonding site within a highly reactive 5′AGTTA* (where* denotes the covalent modification site) sequence in combination with high field proton NMR, we have examined the structure of both the duplex and its covalent adduct. First, we demonstrate the involvement of a bridging water molecule between a phenolic proton on the alkylating subunit of (+)-CC-1065 and an anionic oxygen in the phosphate on the noncovalently modified strand of DNA. This structure has important implications for catalytic activation of the covalent reaction between (+)-CC-1065 and DNA and, consequently, the molecular basis for sequence selective recognition of DNA by the alkylating subunit of (+)-CC-1065. Second, we illustrate the importance of bending and associated conformational flexibility of DNA in the sequence selectivity of the covalent reaction with (+)-CC-1065.

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Author information

Authors and Affiliations

  1. Department of Chemistry, University of Texas at Austin, Austin, Texas, 78712, USA

    C. H. Lin & L. H. Hurley

  2. Drug Dynamics Institute, College of Pharmacy, Austin, Texas, 78712, USA

    L. H. Hurley

Authors
  1. C. H. Lin
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  2. L. H. Hurley
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Editor information

Editors and Affiliations

  1. Polish Academy of Sciences, University of Warsaw, Warsaw, Poland

    David Shugar

  2. Institute of Biochemistry & Biophysics, Polish Academy of Science, 36 Rakowiecka St., 02-532, Warszawa, Poland

    David Shugar

  3. Department of Biophysics, Institute of Experimental Physics, University of Warsaw, 93 Żwirki i Wigury St., 02-089, Warszawa, Poland

    David Shugar

  4. Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteura St., 02-093, Warszawa, Poland

    Wojciech Rode

  5. Department of Pharmaceutical Technology & Biochemistry, Technical University of Gdańsk, 80-952, Gdańsk, Poland

    Edward Borowski

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© 1992 Springer-Verlag Berlin Heidelberg

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Lin, C.H., Hurley, L.H. (1992). Molecular Mechanisms for the Sequence Recognition of DNA by (+)-CC-1065. In: Shugar, D., Rode, W., Borowski, E. (eds) Molecular Aspects of Chemotherapy. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-02740-0_3

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  • DOI: https://doi.org/10.1007/978-3-662-02740-0_3

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-02742-4

  • Online ISBN: 978-3-662-02740-0

  • eBook Packages: Springer Book Archive

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