1axv

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SOLUTION NMR STRUCTURE OF THE [BP]DA ADDUCT OPPOSITE DT IN A DNA DUPLEX, 6 STRUCTURES

Overview

Minor adducts, derived from the covalent binding of, anti-benzo[a]pyrene-7,8-dihydroxy-9,10-epoxide to cellular DNA, may play, an important role in generating mutations and initiating cancer. We have, applied a combined NMR-computational approach including intensity based, refinement to determine the solution structure of the minor, (+)-cis-anti-[BP]dA adduct positioned opposite dT in the, d(C1-T2-C3-T4-C5-[BP]A6-C7-T8-T9-C10-C11)., (d(G12-G13-A14-A15-G16-T17-G18-A19-G20+ ++-A21-G22) 11-mer duplex. The BP, ring system is intercalated toward the 5'-side of the [BP]dA6 lesion site, without disrupting the flanking Watson-Crick dC5.dG18 and [BP]dA6.dT17, base pairs. This structure of the (+)-cis-anti-[BP]dA.dT 11-mer duplex, containing a bay region benzo[a]pyrenyl [BP]dA adduct, is compared with, the corresponding structure of the (+)-trans-anti-[BPh]dA.dT 11-mer duplex, (Cosman et al., Biochemistry 32, 12488-12497, 1993), which contains a, fjord region benzo[c]phenanthrenyl [BPh]dA adduct with the same R, stereochemistry at the linkage site. The carcinogen intercalates toward, the 5'-direction of the modified strand in both duplexes (the adduct is, embedded within the same sequence context) with the buckling of the, Watson-Crick [BP]dA6.dT17 base pair more pronounced in the, (+)-cis-anti-[BP]dA.dT 11-mer duplex compared to its Watson-Crick, [BPh]dA.dT17 base pair in the (+)-trans-anti-[BPh]dA.dT 11-mer duplex. The, available structural studies of covalent polycyclic aromatic hydrocarbon, (PAH) carcinogen-DNA adducts point toward the emergence of a general theme, where distinct alignments are adopted by PAH adducts covalently linked to, the N(6) of adenine when compared to the N(2) of guanine in DNA duplexes., The [BPh]dA and [BP]dA N(6)-adenine adducts intercalate their polycyclic, aromatic rings into the helix without disruption of their modified base, pairs. This may reflect the potential flexibility associated with the, positioning of the covalent tether and the benzylic ring of the carcinogen, in the sterically spacious major groove. By contrast, such an, intercalation without modified base pair disruption option appears not to, be available to [BP]dG N(2)-guanine adducts where the covalent tether and, the benzylic ring are positioned in the more sterically crowded minor, groove. In the case of [BP]dG adducts, the benzopyrenyl ring is either, positioned in the minor groove without base pair disruption, or if, intercalated into the helix, requires disruption of the modified base pair, and displacement of the bases out of the helix.

About this Structure

1AXV is a Protein complex structure of sequences from [1] with BAP as ligand. Full crystallographic information is available from OCA.

Reference

Solution structure of the (+)-cis-anti-benzo[a]pyrene-dA ([BP]dA) adduct opposite dT in a DNA duplex., Mao B, Gu Z, Gorin A, Chen J, Hingerty BE, Amin S, Broyde S, Geacintov NE, Patel DJ, Biochemistry. 1999 Aug 17;38(33):10831-42. PMID:10451380[[Category: benzo[a]pyrene adduct]]

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