The mechanism of topoisomerase I poisoning by a camptothecin analog
The mechanism of topoisomerase I poisoning by a camptothecin analog
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DOI：
10.1073/pnas.242259599
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发表时间：
2002-11-26
影响因子：
11.1
通讯作者：
Stewart, L
中科院分区：
文献类型：
--
作者：
Staker, BL;Hjerrild, K;Stewart, L
我们报告的X-射线晶体结构的人拓扑异构酶I共价连接到双链DNA和绑定到临床批准的抗癌剂拓扑替康。托泊替康模拟DNA碱基对，并通过插入上游（-1）和下游（+1）碱基对之间在DNA切割位点结合。插入置换下游DNA，从而防止切割链的再连接。通过特异性结合酶-底物复合物，托泊替康作为非竞争性抑制剂。该结构可以解释抗癌药物喜树碱家族的几种已知结构-活性关系，并表明至少有两类突变可以产生耐药酶。第一类包括有助于与药物直接相互作用的残基的变化，而第二类将改变与DNA的相互作用，从而使药物结合位点不稳定。
We report the x-ray crystal structure of human topoisomerase I covalently joined to double-stranded DNA and bound to the clinically approved anticancer agent Topotecan. Topotecan mimics a DNA base pair and binds at the site of DNA cleavage by intercalating between the upstream (-1) and downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding to the enzyme-substrate complex, Topotecan acts as an uncompetitive inhibitor. The structure can explain several of the known structure-activity relationships of the camptothecin family of anticancer drugs and suggests that there are at least two classes of mutations that can produce a drug-resistant enzyme. The first class includes changes to residues that contribute to direct interactions with the drug, whereas a second class would alter interactions with the DNA and thereby destabilize the drug-binding site.