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Cleavage behavior of calicheamicin gamma 1 and calicheamicin T.

机译：加利车霉素γ1和加利车霉素T的裂解行为。

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摘要

Calicheamicin gamma 1 is a potent antitumor antibiotic that cleaves DNA with a high degree of specificity; there is much interest in the recognition process. We have investigated the DNA-cleaving properties of calicheamicin T, a truncated derivative of calicheamicin. We show that calicheamicin T cleaves DNA in a double-stranded fashion, indicating that the first two sugars are sufficient to facilitate binding of the aglycone in the minor groove. However, calicheamicin T cleaves DNA nonselectivity. This result suggests that cyclization kinetics do not determine the cleavage specificity of the intact drug. Instead, cleavage specificity probably reflects binding specificity. Because of the recognition sites reported in the original cleavage paper, calicheamicin has been assumed to recognize oligopyrimidine DNA sequences containing G-C base pairs. We show here that calicheamicin also cuts efficiently at A.T tracts, sometimes in preference to G.C-rich homopyrimidine tracts. Crystallographic data and experiments with chemical probes indicate that DNA sequences including G.C base pairs have significantly different local conformations from DNA sequences containing several (four or more) sequential A.T base pairs. This difference makes it unlikely that calicheamicin simply senses inherent groove conformation and suggests that there is some degree of "induced fit." The ability to recognize both A.T- and G.C-rich oligopyrimidine sequences with a high degree of specificity makes calicheamicin an unusual minor-groove binder.
机译：Calicheamicin gamma 1是一种有效的抗肿瘤抗生素，可高度特异性地裂解DNA；人们对识别过程非常感兴趣。我们已经研究了加利车霉素T（加利车霉素的截短衍生物）的DNA切割特性。我们显示加利车霉素T以双链方式切割DNA，表明前两个糖足以促进糖苷配基在小沟中的结合。但是，加利车霉素T切割DNA非选择性。该结果表明环化动力学并不决定完整药物的切割特异性。相反，切割特异性可能反映了结合特异性。由于原始切割论文中报道了识别位点，因此假定加利车霉素可识别含有G-C碱基对的寡嘧啶DNA序列。我们在这里显示加利车霉素还可以在A.T区域有效切割，有时优先于富含G.C的高嘧啶区域。晶体学数据和化学探针实验表明，包括G.C碱基对的DNA序列与含有几个（四个或更多）顺序A.T碱基对的DNA序列具有明显不同的局部构象。这种差异使得加利车霉素不可能简单地感觉到固有的沟槽构形，并暗示存在某种程度的“诱导配合”。能够以高度特异性识别富含A.T和G.C的寡嘧啶序列的能力使加利车霉素成为一种不常见的小沟结合剂。

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