Structure of Nogalamycin Bound to a DNA Hexamer

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 87; no. 6; pp. 2225 - 2229
• Main Authors: Williams, Loren Dean, Egli, Martin, Gao, Qi, Bash, Paul, van der Marel, Gijs A., van Boom, Jacques H., Rich, Alexander, Frederick, Christine A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 01.03.1990; National Acad Sciences
• Subjects: Amino sugars; Anthracyclines; Base Sequence; Biochemistry; Chemical bonding; Crystal structure; Daunorubicin - analogs & derivatives; DNA; Hydrogen Bonding; Hydrogen bonds; Models, Molecular; Molecular Sequence Data; Molecular structure; Molecules; Nogalamycin; Nucleic Acid Conformation; Oligodeoxyribonucleotides; Oxygen; Space life sciences
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.87.6.2225

The anthracycline antibiotic nogalamycin, which binds to DNA, is composed of a planar aglycone substituted on each end to form an unusual dumbbell-shaped molecule. At one end nogalamycin contains an uncharged nogalose sugar and a methyl ester. At the other end nogalamycin contains a positively charged bicyclo amino sugar. We report the crystal structure of nogalamycin bound to the self-complementary DNA hexamer d(m5CGTsAm5CG). In this complex, the cytosines are methylated at the 5 position and the DNA contains a phosphorothioate linkage at the TpA step. Two nogalamycin molecules bind to the 6-base-pair fragment of double-helical DNA. The drug has threaded between the phosphodiester backbones with three aromatic rings intercalated within the DNA. In the major groove, the bicyclo amino sugar forms two direct hydrogen bonds to span a C.G base pair and interacts indirectly with the next base pair of the duplex via a water-mediated hydrogen bond. In the minor groove, a carbonyl oxygen of nogalamycin forms a hydrogen bond directly to N2 of a guanine. The DNA base pairs are severely buckled by up to 26⚬and are also distorted in directions perpendicular to the Watson-Crick hydrogen bonds. This complex illustrates the deformable nature of DNA.