Structural basis for G•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-imidazole polyamides represent the only class of synthetic small molecules that can bind predetermined DNA sequences with affinities and specificities comparable to DNA binding proteins. Antiparallel side-by-side pairings of two aromatic amino acids, imidazole (Im) and pyrrole (Py), distinguish 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 structure 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 minor groove that underlies the pairing rules for DNA recognition.