Structural effects of DNA sequence on T center dot A recognition by hydroxypyrrole/pyrrole pairs in the minor groove

Synthetic polyamides composed of three types of aromatic amino acids, N-met hylimidazole (Im), N-methylpyrrole (Py) and N-methyl-3-hydroxy-pyrrole (Hp) bind specific DNA sequences as antiparallel dimers in the minor groove. Th e side-by-side pairings of aromatic rings in the dimer afford a general rec ognition code that allows all four base-pairs to be distinguished. To exami ne the structural consequences of changing the DNA sequence context on T.A recognition by Hp/Py pairs in the minor groove, crystal structures of polya mide dimers (ImPyHpPy)(2) and the pyrrole counterpart (ImPyPyPy)(2) bound t o the six base-pair target site 5'-AGATCT-3' in a ten base-pair oligonucleo tide have been determined to a resolution of 2.27 and 2.15 Angstrom, respec tively. The structures demonstrate that the principles of Hp/Py recognition of T.A are consistent between different sequence contexts. However, a gene ral structural explanation for the non-additive reduction in binding affini ty due to introduction of the hydroxyl group is less clear. Comparison with other polyamide-DNA cocrystal structures reveals structural themes and dif ferences that may relate to sequence preference. (C) 2000 Academic Press.