Structural investigation of the hedamycin:d(ACCGGT)2 complex by NMR and restrained molecular dynamics.
Hedamycin, a member of the pluramycin family of drugs, displays a range of biological responses including antitumor and antimicrobial activity. The mechanism of action is via direct interaction with DNA through intercalation between the bases of the oligonucleotide and alkylation of a guanine residue at 5'-PyG-3' sites. There appears to be some minor structural differences between two earlier studies on the interaction of hedamycin with 5'-PyG-3' sites. In this study, a high-resolution NMR analysis of the hedamycin:d(ACCGGT)2 complex was undertaken in order to investigate the effect of replacing the thymine with a guanine at the preferred 5'-CGT-3' site. The resultant structure was compared with earlier work, with particular emphasis placed on the drug conformation. The structure of the hedamycin:d(ACCGGT)2 complex has many features in common with the two previous NMR structures of hedamycin:DNA complexes but differed in the conformation and orientation of the N,N-dimethylvancosamine saccharide of hedamycin in one of these structures. The preferential binding of hedamycin to 5'-CG-3' over 5'-TG-3' binding sites is explained in terms of the orientation and location of the N,N-dimethylvancosamine saccharide in the minor groove.
Owen
Elisabeth A
EA
Research School of Chemistry, Australian National University, Canberra, ACT 0200, Australia.
Burley
Glenn A
GA
Carver
John A
JA
Wickham
Geoffrey
G
Keniry
Max A
MA
D000880:Anthraquinones / Q000737:chemistry*; D000903:Antibiotics, Antineoplastic / Q000737:chemistry; D018360:Crystallography, X-Ray; D018736:DNA Adducts / Q000737:chemistry; D004852:Epoxy Compounds / Q000737:chemistry; D007364:Intercalating Agents / Q000737:chemistry; D046911:Macromolecular Substances; D008958:Models, Molecular; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D009690:Nucleic Acid Conformation; D009692:Nucleic Acid Heteroduplexes / Q000737:chemistry; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*; D009844:Oligosaccharides / Q000737:chemistry; D010860:Pigments, Biological / Q000737:chemistry; D012984:Software; D012996:Solutions; D013816:Thermodynamics
D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D018736:DNA Adducts; D004852:Epoxy Compounds; D007364:Intercalating Agents; D046911:Macromolecular Substances; D009692:Nucleic Acid Heteroduplexes; D009838:Oligodeoxyribonucleotides; D009844:Oligosaccharides; D010860:Pigments, Biological; D012996:Solutions; C001328:hedamycin