DNA-drug interactions. The crystal structures of d(TGTACA) and d(TGATCA) complexed with daunomycin.
The anticancer drug daunomycin has been co-crystallized with the hexanucleotide duplex sequences d(TGTACA) and d(TGATCA) and single crystal X-ray diffraction studies of these two complexes have been carried out. Structure solution of the d(TGTACA) and d(TGATCA) complexes to 1.6 and 1.7 Angstrom resolution, respectively, shows two daunomycin molecules bound to the DNA hexamer. Binding occurs via intercalation of the drug chromophore at the d(TpG) step, and hydrogen bonding interactions involving the drug, DNA and solvent molecules. The daunomycin sugar is located in the minor groove of the DNA hexamer and is stabilized by hydrogen bonds between the amino group of the sugar and functional groups on the floor of the groove. The amino sugar of the d(TGATCA) duplex interacts directly with the DNA sequence, while in the d(TGTACA) duplex, the interaction is via solvent molecules. Two other complexes d(CGTACG)-daunomycin and d(CGATCG)-daunomycin have previously been structurally characterized. Comparison of the four structures with daunomycin bound to the triplet sequences 5'TGT, 5'TGA, 5'CGT and 5'CGA reveals changes in the conformation of both the DNA hexamer and the daunomycin upon complexation, as well as the hydrogen bonding and van der Waals' interactions.
Nunn
C M
CM
University Chemical Laboratory, Cambridge, U.K.
Van Meervelt
L
L
Zhang
S D
SD
Moore
M H
MH
Kennard
O
O
D001665:Binding Sites; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003461:Crystallography; D004247:DNA / Q000737:chemistry*; D003630:Daunorubicin / Q000737:chemistry*; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D007364:Intercalating Agents / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D009690:Nucleic Acid Conformation; D012997:Solvents / Q000737:chemistry; D014961:X-Ray Diffraction
D007364:Intercalating Agents; D012997:Solvents; D004247:DNA; D003630:Daunorubicin