Structural Characterization of the 1:1 Adduct Formed between the Antitumor Antibiotic Hedamycin and the Oligonucleotide Duplex d(CACGTG)2 by 2D NMR Spectroscopy
- 1 January 1996
- journal article
- research article
- Published by American Chemical Society (ACS) in Biochemistry
- Vol. 35 (29) , 9314-9324
- https://doi.org/10.1021/bi952542c
Abstract
2D NMR spectroscopic methods have been used to determine the structure of the adduct formed between the antitumor antibiotic hedamycin and the oligodeoxyribonucleotide duplex d(CACGTG)2. Evidence for both intercalation and alkylation in the adduct was observed, and a model for the binding interaction was constructed based on intermolecular NOEs and distance-restrained molecular dynamics. In our computationally refined model, the anthrapyrantrione chromophore of hedamycin is intercalated between the 5'-CG-3' bases with the two aminosugar groups placed in the minor groove and the six carbon bisepoxide side chain located in the major groove. The anglosamine sugar attached at C8 is oriented in the 3' direction relative to the intercalation site, while the N,N-dimethylvancosamine attached at C10 is oriented to the 5' side, with each aminosugar wedged between a guanine exocyclic amino group and one of the groove walls. The terminal epoxide carbon C18 is covalently bound to the N7 atom of the central guanine, as evidenced by lability of the C8 hydrogen of this purine upon reaction with hedamycin. Our binding model places the C10-attached N,N-dimethylvancosamine of hedamycin in van der Waals contact with the alkylated strand. A strong NOE contact verifies the close proximity of the terminal methyl group (C19) of the bisepoxide side chain to the methyl group of the thymine on the 3' side of the alkylated guanine. This, in conjunction with other data, suggests hydrophobic interactions between the bisepoxide chain and the floor of the major groove may contribute to sequence recognition. Furthermore, it is proposed that the 5'-CGT sequence selectivity of hedamycin arises, in part, from complementarity in shape between the chromophore substituents and the major and minor groove at the binding site.Keywords
This publication has 11 references indexed in Scilit:
- Comparison of the sequence selectivity of the DNA-alkylating pluramycin antitumour antibiotics DC92-B and hedamycinChemico-Biological Interactions, 1995
- Altromycin B Threads the DNA Helix Interacting with Both the Major and the Minor Grooves To Position Itself for Site-Directed Alkylation and Guanine N7Journal of the American Chemical Society, 1995
- Interaction of the anthracycline antibiotic nogalamycin with the hexamer duplex d(5′‐GACGTC)2.European Journal of Biochemistry, 1992
- Solution conformation of purine-pyrimidine DNA octamers using nuclear magnetic resonance, restrained molecular dynamics and NOE-based refinementJournal of Molecular Biology, 1990
- Preparation and characterization of an aflatoxin B1 adduct with the oligodeoxynucleotide d(ATCGAT)2Journal of the American Chemical Society, 1989
- Proton and phosphorus-31 NMR investigations of actinomycin D binding selectivity with oligodeoxyribonucleotides containing multiple adjacent d(GC) sitesBiochemistry, 1988
- An all atom force field for simulations of proteins and nucleic acidsJournal of Computational Chemistry, 1986
- Investigation of the solution structures of short nucleic acid fragments by means of nuclear overhauser enhancement measurementsProgress in Nuclear Magnetic Resonance Spectroscopy, 1985
- Principles of Nucleic Acid StructurePublished by Springer Nature ,1984
- Calculations of chemical processes in solutionsThe Journal of Physical Chemistry, 1979