Malina Jaroslav, Vojtiskova Marie, Brabec Viktor, Diakos Connie I, Hambley Trevor W
Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, CZ-61265 Brno, Czech Republic.
Biochem Biophys Res Commun. 2005 Jul 15;332(4):1034-41. doi: 10.1016/j.bbrc.2005.05.047.
The bending, unwinding, and structural changes in DNA caused by the binding of each of the enantiomers of the platinum(II) complexes of the ahaz ligand (R- and S-[PtCl(2)(ahaz)], ahaz=3-aminohexahydroazepine) have been studied using 20-23 bp oligonucleotides containing TGGT and CGGA-binding sites as has the recognition of the adducts by HMG domain proteins. The domain A of HMGB1 (HMGB1a protein) binds to the adduct formed by the R enantiomer at the CGGA sequence with a similar high affinity as it does to the adduct of antitumor cisplatin, and to the adduct formed by the S enantiomer with a slightly lower affinity. In contrast, HMGB1a binds much more weakly to the ahaz adducts than to the cisplatin adducts formed at the TGGT sequence, with the binding to the adduct formed by the R enantiomer being weakest. Each enantiomer and cisplatin cause unwinding of both sequences that is in the narrow range, 19-22 degrees. There are modest but significant differences in the degree of bending induced, with the S enantiomer causing the least bending, cisplatin intermediate, and the R enantiomer the most. Molecular modeling of the {Pt(ahaz)}/GG adducts in 8-bp models reveals significant differences in the local distortion at the GG-binding sites depending on the flanking bases and shows that interactions between the thymine methyl groups and the ahaz ligand are likely to inhibit bending of the TGGT sequence.
已使用含有TGGT和CGGA结合位点的20 - 23碱基对寡核苷酸研究了阿哈兹配体（R - 和S - [PtCl(2)(ahaz)]，ahaz = 3 - 氨基六氢氮杂卓）的铂(II)配合物的各对映体与DNA结合引起的弯曲、解旋及结构变化，以及HMG结构域蛋白对加合物的识别情况。HMGB1的结构域A（HMGB1a蛋白）以与它结合抗肿瘤顺铂加合物相似的高亲和力结合R对映体在CGGA序列处形成的加合物，并以稍低的亲和力结合S对映体形成的加合物。相比之下，HMGB1a与阿哈兹加合物的结合比与在TGGT序列处形成的顺铂加合物的结合弱得多，其中与R对映体形成的加合物的结合最弱。每种对映体和顺铂都会使两个序列解旋，解旋范围较窄，为19 - 22度。在诱导的弯曲程度上存在适度但显著的差异，S对映体引起的弯曲最小，顺铂居中，R对映体最大。在8碱基对模型中对{Pt(ahaz)}/GG加合物进行分子建模，结果显示根据侧翼碱基不同，GG结合位点处的局部扭曲存在显著差异，并且表明胸腺嘧啶甲基基团与阿哈兹配体之间的相互作用可能会抑制TGGT序列的弯曲。
