title: DNA-drug interactions. The crystal structure of d(CGATCG) complexed with daunomycin.
abstract: The structure of a d(CGATCG)-daunomycin complex has been determined by single crystal X-ray diffraction techniques. Refinement, with the location of 40 solvent molecules, using data up to 1.5 A, converged with a final crystallographic residual, R = 0.25 (RW = 0.22). The tetragonal crystals are in space group P4(1)2(1)2, with cell dimensions of a = 27.98 A and c = 52.87 A. The self-complementary d(CGATCG) forms a distorted right-handed helix with a daunomycin molecule intercalated at each d(CpG) step. The daunomycin aglycon chromophore is oriented at right-angles to the long axis of the DNA base-pairs. This head-on intercalation is stabilized by direct hydrogen bonds and indirectly via solvent-mediated, hydrogen-bonding interactions between the chromophore and its intercalation site base-pairs. The cyclohexene ring and amino sugar substituent lie in the minor groove. The amino sugar N-3' forms a hydrogen bond with O-2 of the next neighbouring thymine. This electrostatic interaction helps position the sugar in a way that results in extensive van der Waals contacts between the drug and the DNA. There is no interaction between daunosamine and the DNA sugar-phosphate backbone. We present full experimental details and all relevant conformational parameters, and use the comparison with a d(CGTACG)-daunomycin complex to rationalize some neighbouring sequence effects involved in daunomycin binding.
authors.affiliation: University Chemical Laboratory, Cambridge, U.K.
authors.forename: M H
authors.initials: MH
authors.lastname: Moore
authors.forename: W N
authors.initials: WN
authors.lastname: Hunter
authors.forename: B L
authors.initials: BL
authors.lastname: d'Estaintot
authors.forename: O
authors.initials: O
authors.lastname: Kennard
mesh_terms: D001483:Base Sequence; D004247:DNA / Q000378:metabolism*; D003630:Daunorubicin / Q000378:metabolism*; D006860:Hydrogen Bonding; D046911:Macromolecular Substances; D008958:Models, Molecular; D008968:Molecular Conformation; D009690:Nucleic Acid Conformation; D010455:Peptides / Q000378:metabolism*; D014961:X-Ray Diffraction
chemical_list: D046911:Macromolecular Substances; D010455:Peptides; D004247:DNA; D003630:Daunorubicin