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Nucleic Acids Research, 1990, Vol. 18, No. 18 5533-5541
© 1990

CHEMISTRY

Ternary interactions of spermine with DNA: 4'-epiadriamycin and other DNA: anthracycline complexes

Loren Dean Williams, Christine A. Frederick, Giovanni Ughetto1 and Alexander Rich*

Department of Biology, Massachusetts of Technology Cambridge, MA 02139, USA 1Istituto di Structturistica Chimica, CNR, Area della Ricerca di Roma-Montelibretti Italy

*To whom correspondence should be addressed

Received April 16, 1990. Accepted July 2, 1990.

The recently developed anthracycline 4'-epiadriamycin, an anti-cancer drug with improved activity, differs from adriamycin by inversion of the stereochemistry at the 4'-position. We have cocrystallized 4'-epiadriamycin with the DNA hexamer d(CGATCG) and solved the structure to 1.5 Å resolution using x-ray crystallography. One drug molecule binds at each d(CG) step of the hexamer duplex. The anthracycline sugar binds in the minor groove. A feature of this complex which distinguishes it from the earlier DNA:adriamycin complex is a direct hydrogen bond from the 4'-hydroxyl group of the anthracycline sugar to the adenine N3 on the floor of the DNA minor groove. This hydrogen bond results directly from inversion of the stereochemistry at the 4'-position. Spermine molecules bind in the major groove of this complex. In anthracycline complexes with d(CGATCG) a spermine molecule binds to a continuous hydrophobic zone formed by the 5-methyl and C6 of a thymidine, C5 and C6 of a cytidine and the chromophore of the anthracycline. This report discusses three anthracycline complexes with d(CGATCG) in which the spermine molecules have different conformations yet form extensive van der Waals contacts with the same hydrophobic zone. Our results suggest that these hydrophobic interactions of spermine are DNA sequence specific and provide insight into the question of whether DNA:spermine complexes are delocalized and dynamic or site-specific and static.


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