Abstract
Actinomycin D (AMD) is used clinically to treat tumours such as Wilms' tumour1 and gestational choriocarcinoma2. It inhibits transcription in most cellular systems3,4, and binds to DNA, not to RNA3–5, with a preference for guanine6. The study of the crystal structure of a 2:1 complex between deoxyguanosine and AMD demonstrated both stacking and hydrogen-bonding interactions between the drug and the guanine ring7. Solution studies8,9 have indicated that the drug binds preferentially to guanine–pyrimidine sequences, such as d(GpC), and that an intercalated complex forms with both DNA10 and DNA fragments11. External binding12 and intercalation10,13 models for the structure of the complex between AMD and DNA have been proposed, but until now no crystal strucutre of a complex between AMD and an oligonucleotide has been reported. As the smallest unit of DNA with the potential for forming an intercalated duplex is a self-complementary deoxydinucleoside monophosphate, we undertook the crystallographic analysis of the 2:1 complex between deoxyguanylyl-3′, 5′-deoxycytidine, d(GpC), and AMD. The complex is found to form an unusual pseudo-intercalated structure.
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References
Farber, S. J. Am. med. Ass. 198, 826–836 (1966).
Lewis, J. L. Cancer 30, 1517–1521 (1972).
Goldberg, I. H. & Friedman, P. A. A. Rev. Biochem. 40, 775–810 (1971).
Kersten, H. & Kersten, W. in Inhibitors, of Nucleic Acid Synthesis, 40–66 (Springer, Berlin, 1974).
Bunte, T., Novak, U., Friedrich, R. & Moelling, K. Biochim. biophys. Acta 610, 241–247 (1980).
Goldberg, I. H., Rabinowitz, M. & Reich, E. Proc. natn. Acad. Sci. U.S.A. 48, 2094–2101 (1962).
Sobell, H. M., Jain, S. C., Sakore, T. D. & Nordman, C. E. Nature new Biol. 231, 200–205 (1971).
Krugh, T. R. in Topics in Nucleic Acid Structure (ed. Neidle, S.) 197–217 (Macmillan, London, 1981).
Krugh, T. R. & Chen, Y. C. Biochemistry 14, 4912–4922 (1975).
Müller, W. & Crothers, D. M. J. molec. Biol. 35, 251–290 (1968).
Patel, D. J. Biochemistry 13, 2396–2402 (1974).
Hamilton, L. D., Fuller, W. & Reich, E. Nature 198, 538–540 (1963).
Sobell, H. M. & Jain, S. C. J. molec. Biol. 68, 21–34 (1972).
North, A. C. T., Phillips, D. C. & Mathews, F. S. Acta crystallogr. A24, 351–359 (1968).
Wood, W. “DOCK” Interactive Three Dimensional Display and Manipulation of Molecular and Contour Data (ICR Internal Documentation, Philadelphia, 1981).
Rosenberg, J. M., Seeman, N. C., Day, R. O. & Rich, A. J. molec. Biol. 104, 145–167 (1976).
Seeman, N. C., Rosenberg, J. M., Suddath, F. L., Kim, J. J. P. & Rich, A. J. molec. Biol. 104, 109–144 (1976).
Tsai, C.-C., Jain, S. C. & Sobell, H. M. J. molec. Biol. 114, 301–315 (1977).
Neidle, S. et al. Nature 269, 304–307 (1977).
Wang, A. H. J., Nathans, J., van der Marel, G., van Boom, J. H. & Rich, A. Nature 276, 471–474 (1978).
Berman, H. M. & Young, P. R. A. Rev. Biophys. Bioengng 10, 87–114 (1981).
Seeman, N. C., Day, R. O. & Rich, A. Nature 253, 324–326 (1975).
Reinhardt, C. G. & Krugh, T. R. Biochemistry 16, 2890–2895 (1977).
Patel, D. J. Biochim. biophys. Acta 442, 98–108 (1976).
Patel, D. J. Biopolymers 15, 533–558 (1976).
Quigley, G. J. et al. Proc. natn. Acad. Sci. U.S.A. 77, 7204–7208 (1980).
Broyde, S. & Hingerty, B. Biopolymers 18, 2905–2910 (1979).
Wells, R. D. & Larson, J. E. J. molec. Biol. 49, 319–342 (1970).
Sengupta, S. K. et al. J. med. Chem. 24, 1052–1059 (1981).
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Takusagawa, F., Dabrow, M., Neidle, S. et al. The structure of a pseudo intercalated complex between actinomycin and the DNA binding sequence d(GpC). Nature 296, 466–469 (1982). https://doi.org/10.1038/296466a0
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DOI: https://doi.org/10.1038/296466a0
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