Drug-nucleic acid interaction: X-ray crystallographic determination of an ethidium-dinucleoside monophosphate crystalline complex, ethidium: 5-iodouridylyl(3'-5')adenosine.

The intercalative trypanosomal drug, ethidium bromide, forms a crystalline complex with the dinucleoside monophosphate, 5-iodiuridylyl(3'-5')adenosine (iodoUpA). These crystals are monoclinic, space group C2, with unit cell dimensions, a = 2.845 nm, b = 1.354 nm, c = 3.413 nm, beta = 98.6 degrees. The structure has been solved to atomic resolution by Patterson and Fourier methods, and refined by full matrix least squares to a residual of 0.29 on 2017 observed reflexions. The asymmetric unit contains two ethidium molecules, two iodoUpA molecules, twenty water molecules and four methanol molecules, a total of 156 atims excluding hydrogens. The two iodoUpA molecules are held together by adenine-uracil Watson-Crick base-pairing. Adjacent base-pairs within this paired iodoUpA structure and between neighbouring iodoUpA molecules in adjoining unit cells are separated by 0.68 nm. This separation results from intercalative binding by one ethidium molecule and stacking by the other symmetry is utilized in this model drub-nucleic acid interaction, the intercalative ethidium molecule being oriented such that its phenyl and ethyl groups lie in the narrow groove of the miniature nucleic acid double helix. Solution studies have indicated a marked sequence specificity for ethidium-dinucleotide interactions and a probable structural explanation for this has been provided by this study.