STRUCTURAL BASIS FOR G-CENTER-DOT-C RECOGNITION IN THE DNA MINOR-GROOVE

Small molecules that target specific DNA sequences offer a potentially general approach for the regulation of gene expression. Pyrrole-imida zole polyamides represent the only class of synthetic small molecules that can bind predetermined DNA sequences with affinities and specific ities comparable to DNA binding proteins. Antiparallel side-by-side pa irings of two aromatic amino acids, imidazole (Im) and pyrrole (Py), d istinguish G-center-dot-C from C-center-dot-G, and both from A-center- dot-T/T-center-dot-A base pairs. A high resolution x-ray crystal struc ture of a four-ring pyrrole-imidazole polyamide specifically bound as a dimer to a six-base pair predetermined DNA site reveals a structural framework of hydrogen bonds and interactions with the walls of the mi nor groove that underlies the pairing rules for DNA recognition.