The carcinogenic heterocyclic
amine (HA) 2-amino-1-methyl-6-phenylimidazo[4,5-
b]pyridine (
PhIP) is formed during the cooking of various meats. To enable structure/activity studies aimed at understanding how
DNA damaged by a member of the HA class of compounds can ultimately lead to
cancer, we have determined the first
solution structure of an 11-mer duplex containing the C8-dG adduct formed by reaction with
N-acetoxy-PhIP. A slow conformational exchange is observed in which the
PhIP ligand either intercalates into the
DNA helix by denaturing and displacing the modified base pair (main form) or is located outside the helix in a minimally perturbed
B-DNA duplex (minor form). In the main base-displaced intercalation structure, the minor groove is widened, and the major groove is compressed at the lesion site because of the location of the bulky
PhIP-N-methyl and phenyl ring in the minor groove; this distortion causes significant bending of the helix. The
PhIP phenyl ring interacts with the phosphodiester-
sugar ring backbone of the complementary strand and its fast rotation with respect to the intercalated
imidazopyridine ring causes substantial distortions at this site, such as unwinding and bulging-out of the strand. The glycosidic torsion angle of the [
PhIP]dG residue is syn, and the displaced
guanine base is directed toward the 3' end of the modified strand. This study contributes, to our knowledge, the first structural information on the biologically relevant HA class to a growing body of knowledge about how conformational similarities and differences for a variety of types of lesions can influence
protein interactions and ultimately
biological outcome.