Solution structure of the 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine C8-deoxyguanosine adduct in duplex DNA

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 enab le structure/activity studies aimed at understanding how DNA damaged by a m ember of the HA class of compounds can ultimately lead to cancer, we have d etermined the first solution structure of an Il-mer duplex containing the C 8-dG adduct formed by reaction with N-acetoxy-PhIP. A slow conformational e xchange is observed in which the PhIP ligand either intercalates into the D NA 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 gro ove; this distortion causes significant bending of the helix. The PhIP phen yl ring interacts with the phosphodiester-sugar ring backbone of the comple mentary strand and its fast rotation with respect to the intercalated imida zopyridine ring causes substantial distortions at this site, such as unwind ing and bulging-out of the strand. The glycosidic torsion angle of the [PhI P]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, t he first structural information on the biologically relevant HA class to a growing body of knowledge about how conformational similarities and differe nces for a variety of types of lesions can influence protein interactions a nd ultimately biological outcome.