CRYSTAL-STRUCTURE OF D(CGCGAATTCGCG) COMPLEXED WITH PROPAMIDINE, A SHORT-CHAIN HOMOLOG OF THE DRUG PENTAMIDINE

The crystal structure of the complex between propamidine and the self- complementary DNA dodecamer d(CGCGAATTCGCG) duplex has been determined to a resolution of 2.1 angstrom and an R-factor of 17.4%. The propami dine binds to the DNA within the minor groove, with specific hydrogen- bonding interactions from the amidinium groups to the bases and sugar groups of the DNA, via a 4-base-pair binding site. A network of water molecules lies over the mouth of the minor groove. The structure provi des a rationale for the superior DNA-binding properties of propamidine as compared to pentamidine [cf. Edwards, K. J., Jenkins, T. C., & Nei dle, S. (1992) Biochemistry 31, 7104-7109]. This is seen to result fro m (i) decreased minor groove width at the binding site and (ii) reduce d mobility of the bound propamidine molecule.