Giri Indrajit, Jenkins Mark D, Schnetz-Boutaud Nathalie C, Stone Michael P
Department of Chemistry and Center in Molecular Toxicology, Vanderbilt University, Nashville, Tennessee 37235, USA.
Chem Res Toxicol. 2002 May;15(5):638-47. doi: 10.1021/tx010187n.
The structure of the cationic 8,9-dihydro-8-(N7-guanyl)-9-hydroxy-aflatoxin B(1) adduct embedded in a 5'-CpG-3' sequence context and paired with deoxycytosine in the oligodeoxynucleotide d(ACATC(AFB)GATCT) x d(AGATCGATGT) was refined using molecular dynamics calculations restrained by NOE data and dihedral angle restraints obtained from NMR data. The aflatoxin moiety intercalated above the 5' face of the modified guanine. It stacked between C(5) x G(16) and (AFB)G(6) x C(15). The AFB(1) H5, OCH(3), and methylene protons faced into the minor groove, with the methylene protons oriented between the C(15) and G(16) nucleobases. The aflatoxin B(1) H6a, H8, H9, and H9a protons faced the major groove, with H6a and H9a pointing toward the 5' direction from the lesion site. The refined structure was compared to the structure of the aflatoxin B(1) adduct embedded in a 5'-ATGCAT-3' sequence in the oligodeoxynucleotide d(TAT(AFB)GCATA)(2) [Jones, W. R., Johnston, D. S., and Stone, M. P. (1998) Chem. Res. Toxicol.11, 873-881]. The structure of the intercalated aflatoxin B(1) lesion in the ATC(AFB)GAT sequence is similar to its structure in the d(AT(AFB)GCAT) sequence. This is consistent with a mechanism in which the precovalent intercalation of aflatoxin-8,9-exo-epoxide on the 5' face of guanine places the epoxide in close proximity and in the proper orientation to the N7 position of guanine, thus facilitating an S(N)2 reaction. The data provides additional insight into the nature of the disruption of the B-DNA duplex induced by aflatoxin B(1) intercalation. Overall, the results suggest that sequence contributes a minor role in modulating the structure of the cationic guanine N7 AFB(1) lesion in duplex DNA. On the other hand, structural differences are observed when the correctly paired structure is compared to the structure of the cationic AFB(1) adduct mispaired with dA [Giri, I., Johnston, D. S., and Stone, M. P. (2002) Biochemistry 41, 5462-5472].
嵌入在5'-CpG-3'序列环境中并与寡脱氧核苷酸d(ACATC(AFB)GATCT)×d(AGATCGATGT)中的脱氧胞嘧啶配对的阳离子8,9-二氢-8-(N7-鸟嘌呤基)-9-羟基黄曲霉毒素B(1)加合物的结构，使用由NOE数据和从NMR数据获得的二面角约束限制的分子动力学计算进行了优化。黄曲霉毒素部分插入到修饰鸟嘌呤的5'面上方。它堆积在C(5)×G(16)和(AFB)G(6)×C(15)之间。AFB(1)的H5、OCH(3)和亚甲基质子面向小沟，亚甲基质子位于C(15)和G(16)核碱基之间。黄曲霉毒素B(1)的H6a、H8、H9和H9a质子面向大沟，H6a和H9a从损伤位点指向5'方向。将优化后的结构与寡脱氧核苷酸d(TAT(AFB)GCATA)(2)中嵌入在5'-ATGCAT-3'序列中的黄曲霉毒素B(1)加合物的结构进行了比较[琼斯，W.R.，约翰斯顿，D.S.，和斯通，M.P.(1998)《化学研究毒理学》11, 873 - 881]。ATC(AFB)GAT序列中插入的黄曲霉毒素B(1)损伤的结构与其在d(AT(AFB)GCAT)序列中的结构相似。这与一种机制一致，即黄曲霉毒素-8,9-外环氧化物在鸟嘌呤的5'面的预共价插入将环氧化物置于与鸟嘌呤的N7位置紧密接近且方向合适的位置，从而促进S(N)2反应。这些数据为黄曲霉毒素B(1)插入诱导的B-DNA双链体破坏的性质提供了更多见解。总体而言，结果表明序列在调节双链DNA中阳离子鸟嘌呤N7 AFB(1)损伤的结构方面起次要作用。另一方面，当将正确配对的结构与与dA错配的阳离子AFB(1)加合物的结构进行比较时，观察到了结构差异[吉里，I.，约翰斯顿，D.S.，和斯通，M.P.(2002)《生物化学》41, 5462 - 5472]。
