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•C from C•G, and both from A•T/T•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