The @entity69910 intrastrand DNA cross-link arises from the bis-alkylation of tandem N(6)-dA sites in DNA by R,R-butadiene diepoxide (BDO(2)). The oligodeoxynucleotide 5'-d(C(1)G(2)G(3)A(4)C(5)X(6)Y(7)G(8)A(9)A(10)G(11))-3'.5'-d(C(12)T(13)T(14)C(15)T(16)T(17)G(18)T(19)C(20)C(21)G(22))-3' contains the BDO(2) cross-link between the second and third adenines of the codon 61 sequence (underlined) of the @entity1 @entity8497 protooncogene and is named the (S,S)-BD-(61-2,3) cross-link (X,Y = cross-linked adenines). NMR analysis reveals that the cross-link is oriented in the major groove of duplex DNA. @entity1264 pairing is perturbed at base pair X(6).T(17), whereas base pairing is intact at base pair Y(7).T(16). The cross-link appears to exist in two conformations, in rapid exchange on the NMR time scale. In the first conformation, the beta-OH is predicted to form a @entity3884 bond with T(16) O(4), whereas in the second, the beta-OH is predicted to form a @entity3884 bond with T(17) O(4). In contrast to the (R,R)-BD-(61-2,3) cross-link in the same sequence (Merritt, W. K., Nechev, L. V., Scholdberg, T. A., Dean, S. M., Kiehna, S. E., Chang, J. C., Harris, T. M., Harris, C. M., Lloyd, R. S., and Stone, M. P. (2005) Biochemistry 44, 10081-10092), the anti-conformation of the two @entity3787 groups at C(beta) and C(gamma) with respect to the C(beta)-C(gamma) bond results in a decreased twist between base pairs X(6).T(17) and Y(7).T(16), and an approximate 10 degrees bending of the duplex. These conformational differences may account for the differential mutagenicity of the (S,S)- and (R,R)-BD-(61-2,3) cross-links and suggest that stereochemistry plays a role in modulating biological responses to these cross-links (Kanuri, M., Nechev, L. V., Tamura, P. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2002) Chem. Res. Toxicol. 15, 1572-1580).

Structure of the XXXX intrastrand DNA cross-link arising from butadiene diepoxide in the @entity1 @entity8497 codon 61 sequence.

@entity1 :: ('9606', 'Species') :: ['human'] @entity3884 :: ('MESH:D006859', 'Chemical') :: ['hydrogen'] @entity1264 :: ('MESH:D009456', 'Disease') :: ['Watson-Crick base'] @entity3787 :: ('MESH:D017665', 'Chemical') :: ['hydroxyl'] @entity8497 :: ('4893', 'Gene') :: ['N-ras'] @entity69910 :: ('MESH:C519532', 'Chemical') :: ["1,4-bis(2'-deoxyadenosin-N(6)-yl)-2S,3S-butanediol"]
@entity69910 :: (MESH:C519532,Chemical) :: ['1,4-Bis(2'-deoxyadenosin-N(6)-yl)-2S,3S-butanediol']
