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. 1998 Jun 15;26(12):3001–3005. doi: 10.1093/nar/26.12.3001

Binding of the modified daunorubicin WP401 adjacent to a T-G base pair induces the reverse Watson-Crick conformation: crystal structures of the WP401-TGGCCG and WP401-CGG[br5C]CG complexes.

R Dutta 1, Y G Gao 1, W Priebe 1, A H Wang 1
PMCID: PMC147649  PMID: 9611247

Abstract

2'-Bromo-4'-epi-daunorubicin (alpha-manno configuration, denoted WP401) is a new anthracycline drug that exhibits promising activity toward multidrug-resistant cancer cells. We carried out X-ray diffraction analyses of the complexes formed in the presence of formaldehyde between WP401 and two DNA hexamers, TGGCCG and CGG[br5C]CG. The two complexes crystallized in different crystal lattices with respective crystal data of space group P4322, a = b = 37.20 A, c = 70.53 A and space group P43212, a = b = 37.23 A, c = 61. 96 A. These new crystal forms are different from the P41212 form of other daunorubicin/doxorubicin complexes studied previously. The refined crystal structures at approximately 2.0 A resolution revealed that the entire 2:1 drug-DNA complex is in the asymmetrical unit. Two WP401 drug molecules bind to the duplex, with the aglycones intercalated between the CpG or TpG steps and their modified daunosamines in the minor groove. As observed earlier, in the presence of formaldehyde, WP401 more readily forms a covalent adduct with (C/T)GG*:CCG than with (C/T)GC:G*CG (G* is the crosslink site), the opposite of what is seen for daunorubicin and doxorubicin. Surprisingly, the two T-G mismatched base pairs in the WP401-TGGCCG complex adopt the reverse Watson-Crick conformation, instead of the wobble conformation. The unusual T-G reverse Watson-Crick conformation may be required in order to maintain favorable stacking interactions between the base pair and the aglycone of WP401. Our results show that chemical modifications like bromo or iodo substitution on anthracycline drugs have significant effects on their DNA binding properties.

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Selected References

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  1. Caceres-Cortes J., Wang A. H. Binding of the antitumor drug nogalamycin to bulged DNA structures. Biochemistry. 1996 Jan 16;35(2):616–625. doi: 10.1021/bi9518398. [DOI] [PubMed] [Google Scholar]
  2. Chaires J. B., Satyanarayana S., Suh D., Fokt I., Przewloka T., Priebe W. Parsing the free energy of anthracycline antibiotic binding to DNA. Biochemistry. 1996 Feb 20;35(7):2047–2053. doi: 10.1021/bi952812r. [DOI] [PubMed] [Google Scholar]
  3. Denny W. A. DNA-intercalating ligands as anti-cancer drugs: prospects for future design. Anticancer Drug Des. 1989 Dec;4(4):241–263. [PubMed] [Google Scholar]
  4. Gao Y. G., Liaw Y. C., Li Y. K., van der Marel G. A., van Boom J. H., Wang A. H. Facile formation of a crosslinked adduct between DNA and the daunorubicin derivative MAR70 mediated by formaldehyde: molecular structure of the MAR70-d(CGTnACG) covalent adduct. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4845–4849. doi: 10.1073/pnas.88.11.4845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Gao Y. G., Priebe W., Wang A. H. Substitutions at C2' of daunosamine in the anticancer drug daunorubicin alter its DNA-binding sequence specificity. Eur J Biochem. 1996 Sep 1;240(2):331–335. doi: 10.1111/j.1432-1033.1996.0331h.x. [DOI] [PubMed] [Google Scholar]
  6. Kresnak M. T., Davidson R. L. Thymidine-induced mutations in mammalian cells: sequence specificity and implications for mutagenesis in vivo. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2829–2833. doi: 10.1073/pnas.89.7.2829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Parkinson G., Vojtechovsky J., Clowney L., Brünger A. T., Berman H. M. New parameters for the refinement of nucleic acid-containing structures. Acta Crystallogr D Biol Crystallogr. 1996 Jan 1;52(Pt 1):57–64. doi: 10.1107/S0907444995011115. [DOI] [PubMed] [Google Scholar]
  8. Robinson H., Priebe W., Chaires J. B., Wang A. H. Binding of two novel bisdaunorubicins to DNA studied by NMR spectroscopy. Biochemistry. 1997 Jul 22;36(29):8663–8670. doi: 10.1021/bi970842j. [DOI] [PubMed] [Google Scholar]
  9. Smith C. K., Davies G. J., Dodson E. J., Moore M. H. DNA-nogalamycin interactions: the crystal structure of d(TGATCA) complexed with nogalamycin. Biochemistry. 1995 Jan 17;34(2):415–425. doi: 10.1021/bi00002a005. [DOI] [PubMed] [Google Scholar]
  10. Stassinopoulos A., Ji J., Gao X., Goldberg I. H. Solution structure of a two-base DNA bulge complexed with an enediyne cleaving analog. Science. 1996 Jun 28;272(5270):1943–1946. doi: 10.1126/science.272.5270.1943. [DOI] [PubMed] [Google Scholar]
  11. Taatjes D. J., Gaudiano G., Koch T. H. Production of formaldehyde and DNA-adriamycin or DNA-daunomycin adducts, initiated through redox chemistry of dithiothreitol/iron, xanthine oxidase/NADH/iron, or glutathione/iron. Chem Res Toxicol. 1997 Sep;10(9):953–961. doi: 10.1021/tx970064w. [DOI] [PubMed] [Google Scholar]
  12. Taatjes D. J., Gaudiano G., Resing K., Koch T. H. Redox pathway leading to the alkylation of DNA by the anthracycline, antitumor drugs adriamycin and daunomycin. J Med Chem. 1997 Apr 11;40(8):1276–1286. doi: 10.1021/jm960835d. [DOI] [PubMed] [Google Scholar]
  13. Wang A. H., Gao Y. G., Liaw Y. C., Li Y. K. Formaldehyde cross-links daunorubicin and DNA efficiently: HPLC and X-ray diffraction studies. Biochemistry. 1991 Apr 23;30(16):3812–3815. doi: 10.1021/bi00230a002. [DOI] [PubMed] [Google Scholar]
  14. Wang A. H., Ughetto G., Quigley G. J., Rich A. Interactions between an anthracycline antibiotic and DNA: molecular structure of daunomycin complexed to d(CpGpTpApCpG) at 1.2-A resolution. Biochemistry. 1987 Feb 24;26(4):1152–1163. doi: 10.1021/bi00378a025. [DOI] [PubMed] [Google Scholar]

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