Chakrabarti S, Dasgupta D
Biophysics Division, Saha Institute of Nuclear Physics, 37, Belgachhia Road, Calcutta 700 037, India.
Indian J Biochem Biophys. 2001 Feb-Apr;38(1-2):64-70.
Anti-cancer antibiotics, chromomycin A3 (CHR) and mithramycin (MTR) inhibit DNA directed RNA synthesis in vivo by binding reversibly to template DNA in the minor groove with GC base specificity, in the presence of divalent cations like Mg2+. Under physiological conditions, (drug)2Mg2+ complexes formed by the antibiotics are the potential DNA binding ligands. Structures of CHR and MTR differ in their saccharide residues. Scrutiny of the DNA binding properties reveal significant differences in their sequence selectivity, orientation and stoichiometry of binding. Here, we have analyzed binding and thermodynamic parameters for the interaction of the antibiotics with a model oligonucleotide sequence, d(TAGCTAGCTA)2 to understand the role of sugars. The oligomer contains two potential binding sites (GpC) for the ligands. The study illustrates that the drugs bind differently to the sequence. (MTR)2Mg2+ binds to both sites whereas (CHR)2Mg2+ binds to a single site. UV melting profiles for the decanucleotide saturated with the ligands show that MTR bound oligomer is highly stabilized and melts symmetrically. In contrast, with CHR, loss of symmetry in the oligomer following its association with a single (CHR)2Mg2+ complex molecule leads to a biphasic melting curve. Results have been interpreted in the light of saccharide dependent differences in ligand flexibility between the two antibiotics.
抗癌抗生素色霉素A3（CHR）和光辉霉素（MTR）在体内通过在二价阳离子（如Mg2+）存在的情况下，以GC碱基特异性可逆地结合到小沟中的模板DNA上，从而抑制DNA指导的RNA合成。在生理条件下，抗生素形成的（药物）2Mg2+复合物是潜在的DNA结合配体。CHR和MTR的结构在其糖残基上有所不同。对DNA结合特性的仔细研究揭示了它们在序列选择性、结合方向和化学计量方面的显著差异。在这里，我们分析了抗生素与模型寡核苷酸序列d(TAGCTAGCTA)2相互作用的结合和热力学参数，以了解糖的作用。该寡聚物含有两个潜在的配体结合位点（GpC）。研究表明，药物与该序列的结合方式不同。（MTR）2Mg2+与两个位点结合，而（CHR）2Mg2+只与一个位点结合。用配体饱和的十聚体的紫外熔解曲线表明，MTR结合的寡聚物高度稳定且对称熔解。相比之下，对于CHR，寡聚物与单个（CHR）2Mg2+复合分子结合后对称性的丧失导致了双相熔解曲线。根据两种抗生素之间配体灵活性的糖依赖性差异对结果进行了解释。
