Sun D, Hurley L H
Drug Dynamics Institute, College of Pharmacy, University of Texas at Austin, 78712-1074.
Gene. 1994 Nov 4;149(1):165-72. doi: 10.1016/0378-1119(94)90425-1.
The effect of the antitumor antibiotic (+)-CC-1065 on the binding of Sp1 to the 21-bp repeats of SV40 DNA has been investigated. (+)-CC-1065 alkylates N3 of adenine in DNA and resides in the minor groove. As a consequence of alkylation of the two 5'-AGTTA* sequences (* indicates covalent modification site), which reside between GC boxes III and IV, and boxes V and VI, protein binding to the 3' sites is completely abolished and there is a significant decrease in Sp1 binding to the other regions. The effect of substituting A5 tracts for the (+)-CC-1065-bonding sequence was intermediate between the unmodified 5'-AGTTA* and the drug-modified sequences. It is proposed that a structural distortion of DNA associated with stiffening of the helix induced by the drug-adduct formation is primarily responsible for the inhibition of binding of Sp1 molecules to 21-bp repeats, rather than steric hindrance due to the occupancy by drug molecules of the minor groove within that region.
已研究了抗肿瘤抗生素（+）-CC-1065对Sp1与SV40 DNA的21碱基对重复序列结合的影响。（+）-CC-1065使DNA中的腺嘌呤N3烷基化，并位于小沟中。由于位于GC框III和IV之间以及框V和VI之间的两个5'-AGTTA*序列（表示共价修饰位点）发生烷基化，与3'位点的蛋白质结合完全被消除，并且Sp1与其他区域的结合显著减少。用A5序列替代（+）-CC-1065结合序列的效果介于未修饰的5'-AGTTA和药物修饰序列之间。有人提出，与药物加合物形成诱导的螺旋变硬相关的DNA结构扭曲主要是Sp1分子与21碱基对重复序列结合受抑制的原因，而不是由于该区域小沟被药物分子占据所导致的空间位阻。
