Visualization of drug-nucleic acid interactions at atomic resolution: VI. Structure of two drug-dinucleoside monophosphate crystalline complexes, ellipticine-5-iodocytidylyl (3′–5′) guanosine and 3,5,6,8-tetramethyl- n-methyl phenanthrolinium-5-iodocytidylyl (3′–5′) guanosine

Abstract

Ellipticine and 3,5,6,8-tetramethyl- N-methyl phenanthrolinium form complexes with the dinucleoside monophosphate, 5-iodocytidylyl(3′–5′)guanosine. These crystals are isomorphous: ellipticine-iodoCpG † † Abbreviations used: iodoCpG, 5-iodocytidylyl(3′–5′)guanosine; TMP, 3,5,6,8-tetramethyl- N-methyl phenanthrolinium. crystals are monoclinic, space group P2 1 with a = 13.88 A ̊ , b = 19.11 A ̊ , c = 21.42 A ̊ , β = 105.4; TMP-iodoCpG crystals are monoclinic, space group P2 1, with a = 13.99 A ̊ , b = 19.12 A ̊ , c = 21.31 A ̊ , β = 104.9 °. Both structures have been solved to atomic resolution by Patterson and Fourier methods, and refined by full matrix least-squares. The asymmetric unit in the ellipticine-iodoCpG structure contains two ellipticine molecules, two iodoCpG molecules, 20 water molecules and 2 methanol molecules, a total of 144 atoms, whereas, in the tetramethyl- N-methyl phenanthrolinium-iodoCpG complex, the asymmetric unit contains two TMP molecules, two iodoCpG molecules, 17 water molecules and 2 methanol molecules, a total of 141 atoms. In both structures, the two iodoCpG molecules are hydrogenbonded together by guanine-cytosine Watson-Crick base-pairing. Adjacent base-pairs within this paired iodoCpG structure are separated by about 6.7 Å; this separation results from intercalative binding by one ellipticine (or TMP) molecule and stacking by the other ellipticine (or TMP) molecule above or below the base-pairs. Base-pairs within the paired nucleotide units are related by a twist of 10 to 12 °. The magnitude of this angular twist is related to conformational changes in the sugar-phosphate chains that accompany drug intercalation. These changes partly reflect the mixed sugar puckering pattern observed: C3′ endo (3′–5′) C2′ endo (i.e. both iodocytidine residues have C3′ endo conformations, whereas both guanosine residues have C2′ endo conformations), and additional small but systematic changes in torsional angles that involve the phosphodiester linkages and the C4′C5′ bond. The stereochemistry observed in these model drug-nucleic acid intercalative complexes is almost identical to that observed in the ethidium-iodoUpA and -iodoCpG complexes determined previously (Tsai et al., 1975 a,b,1977; Jain et al., 1977). This stereochemistry is also very similar to that observed in the 9-aminoacridine-iodoCpG and acridine orange-iodoCpG complexes described in the preceding papers (Sakore et al., 1979 Reddy et al., 1979). We have already proposed this stereochemistry to provide a unified understanding of a large number of intercalative drug-DNA (and RNA) interactions (Sobell et al., 1977 a,b), and discuss this aspect of our work further in this paper.