Structural basis for recognition of 5′-phosphotyrosine adducts by Tdp2
Structural basis for recognition of 5′-phosphotyrosine adducts by Tdp2
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DOI：
10.1038/nsmb.2423
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发表时间：
2012-12-01
影响因子：
16.8
通讯作者：
Aihara, Hideki
中科院分区：
文献类型：
--
作者：
Shi, Ke;Kurahashi, Kayo;Aihara, Hideki
DNA修复酶Tdp2分解5'-磷酸酪氨酸DNA加合物并介导对靶向共价拓扑异构酶-DNA复合物的抗癌药物的耐药性。Tdp2还参与发育和肿瘤发生过程中的关键信号通路，并在小核糖核酸病毒复制过程中切割蛋白质- rna连锁。斑马鱼Tdp2与DNA结合的晶体结构显示出一个深而窄的基本凹槽，选择性地容纳单链DNA的5'端，形成拉伸构象。全长秀丽隐杆线虫Tdp2的晶体结构表明，该沟槽在体外也可以容纳酸性肽拉伸，谷氨酸和天冬氨酸侧链占据DNA主干磷酸结合位点。这种广泛的分子模仿表明Tdp2与磷酸化蛋白在信号传导中的自动调节和相互作用的潜在机制。我们的研究为探究Tdp2的功能和开发用于化疗和抗病毒应用的抑制剂提供了一个框架。
The DNA-repair enzyme Tdp2 resolves 5'-phosphotyrosyl DNA adducts and mediates resistance to anticancer drugs that target covalent topoisomerase-DNA complexes. Tdp2 also participates in key signaling pathways during development and tumorigenesis and cleaves a protein-RNA linkage during picornavirus replication. The crystal structure of zebrafish Tdp2 bound to DNA reveals a deep, narrow basic groove that selectively accommodates the 5' end of single-stranded DNA in a stretched conformation. The crystal structure of the full-length Caenorhabditis elegans Tdp2 shows that this groove can also accommodate an acidic peptide stretch in vitro, with glutamate and aspartate side chains occupying the DNA backbone phosphate-binding sites. This extensive molecular mimicry suggests a potential mechanism for autoregulation and interaction of Tdp2 with phosphorylated proteins in signaling. Our study provides a framework to interrogate functions of Tdp2 and develop inhibitors for chemotherapeutic and antiviral applications.