STUDIES OF BINDING OF ACTINOMYCIN AND RELATED COMPOUNDS TO DNA
STUDIES OF BINDING OF ACTINOMYCIN AND RELATED COMPOUNDS TO DNA
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DOI：
10.1016/s0022-2836(68)80024-5
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发表时间：
1968-01-01
影响因子：
5.6
通讯作者：
CROTHERS, DM
中科院分区：
文献类型：
--
作者：
MULLER, W;CROTHERS, DM
放线菌素及其衍生物和一些更简单的类似物与小牛胸腺、细菌和梨状四膜虫DNA结合的平衡、动力学和流体动力学研究报道。放线菌素发色团插在DNA复合体的碱基对之间。结合可以发生在任何GC[鸟嘌呤-胞嘧啶]对附近，但在给定位点结合会产生螺旋扭曲，这极大地不利于6个碱基对以外的另一个放线菌素的结合。螺旋畸变的来源可能是脱氧核糖环氧和附在发色团上的- conh -基团之间形成的一对氢键。鸟嘌呤在常见碱基中的特异性是由于在插层结构中形成的[pi]-络合物中的电子相互作用。放线菌素与简单芳香体系之间复杂形成的研究使这一结论可信。几种形式的络合物在平衡状态下存在；这是由于放线菌素的环状肽环的构象变化。在最稳定的复合物形式中，肽环经历了构象变化，使其结构适应与DNA主链特异性相互作用，一个环与双螺旋的每条链相互作用。将放线菌素与简单的类似物（缺乏生物活性）区分开来的物理性质是非常缓慢的解离反应，比非活性类似物慢几个数量级。缓慢解离的结构基础是肽环构象变化的缓慢逆转。含有5个氨基酸的肽环可能被选择用于此功能，因为这种紧密排列的结构固有的构象变化具有很大的空间位阻。
Equilibrium, kinetic and hydrodynamic studies are reported of the binding to [calf thymus, bacterial and Tetrahymena pyriformis] DNA of actinomycin, its derivatives, and some simpler analogs. The actinomycin chromophore is intercalated between the base pairs in the DNA complex. Binding can occur adjacent to any GC [guanine-cytosine] pair, but binding at a given site produces a distortion of the helix that greatly disfavors binding of another actinomycin closer than 6 base pairs away. The source of the helix distortion is probably a pair of hydrogen bonds formed between the deoxyribose ring oxygens and the -CONH- groups attached to the chromophore. The specificity for guanine among the common bases results from electronic interactions in the [pi]-complex formed in an intercalated structure. Studies of complex formation between actinomycin and simple aromatic systems make this conclusion plausible. Several forms of the complex exist at equilibrium; these result from conformational changes within the cyclic peptide rings of actinomycin. In the most stable form of the complex, the peptide rings have undergone conformational changes which adapt their structures to interact specifically with the DNA backbone, one ring interacting with each strand of the double helix. The physical property which distinguished actinomycin from the simpler analogs (which lack biological activity) is a very slow dissociation reaction, several orders of magnitude slower than for the non-active analogs. The structural basis for the slow dissociation is the slow reversal of the conformational change of the peptide rings. The peptide ring containing 5 amino acids is probably selected for this function because of the great steric hindrance to conformational changes inherent in such a tightly packed structure.