SEQUENCE-DEPENDENT DRUG-BINDING TO THE MINOR-GROOVE OF DNA - CRYSTAL-STRUCTURE OF THE DNA DODECAMER D(CGCAAATTTGCG)(2) COMPLEXED WITH PROPAMIDINE

DNA-binding ligand propamidine, an analogue of the drug pentamidine wh ich is used in the treatment of acquired immune deficiency syndrome (A IDS)-associated Pneumocystis carinii, has been cocrystallized with the DNA sequence d(CGCAAATTTGCG)(2), and the crystal structure of the com plex has been determined using data from 8 to 2.2 Angstrom resolution. The R factor converged to 15.5% with the inclusion of 73 water molecu les. The structure shows binding of the propamidine molecule within th e AT tract of the DNA minor groove with a shift from the center of the duplex toward the 3' end of ca. 2 Angstrom. The long AT tract of six base pairs in length allows the propamidine many potential binding sit es in the DNA groove, and its binding is seen to occur where there is least perturbation to the DNA from that seen in the native structure. The interactions with bases are distinct from those previously observe d for the sequence d(CGCGAATTCGCG)(2).