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Structural Characterization of a Viral NEIL1 Ortholog Unliganded and Bound to Abasic Site-containing DNA

机译:病毒NEIL1直向同源物的未结合和绑定到含基本位点的DNA的结构表征。

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摘要

Endonuclease VIII (Nei) is a DNA glycosylase of the base excision repair pathway that recognizes and excises oxidized pyrimidines. We determined the crystal structures of a NEIL1 ortholog from the giant Mimivirus (MvNei1) unliganded and bound to DNA containing tetrahydrofuran (THF), which is the first structure of any Nei with an abasic site analog. The MvNei1 structures exhibit the same overall architecture as other enzymes of the Fpg/Nei family, which consists of two globular domains joined by a linker region. MvNei1 harbors a zincless finger, first described in human NEIL1, rather than the signature zinc finger generally found in the Fpg/Nei family. In contrast to Escherichia coli Nei, where a dramatic conformational change was observed upon binding DNA, the structure of MvNei1 bound to DNA does not reveal any substantial movement compared with the unliganded enzyme. A protein segment encompassing residues 217–245 in MvNei1 corresponds to the “missing loop” in E. coli Nei and the “αF–β10 loop” in E. coli Fpg, which has been reported to be involved in lesion recognition. Interestingly, the corresponding loop in MvNei1 is ordered in both the unliganded and furan-bound structures, unlike other Fpg/Nei enzymes where the loop is generally ordered in the unliganded enzyme or in complexes with a lesion, and disordered otherwise. In the MvNei1·tetrahydrofuran complex a tyrosine located at the tip of the putative lesion recognition loop stacks against the furan ring; the tyrosine is predicted to adopt a different conformation to accommodate a modified base.
机译:核酸内切酶VIII(Nei)是碱基切除修复途径的DNA糖基化酶,可识别并切除氧化的嘧啶。我们确定了巨型Mimivirus(MvNei1)的NEIL1直系同源物的晶体结构,该结构未经配体并结合到含有四氢呋喃(THF)的DNA,这是任何带有无碱基位点类似物的Nei的第一结构。 MvNei1结构展示了与Fpg / Nei家族其他酶相同的总体结构,该酶由通过接头区域连接的两个球形结构域组成。 MvNei1带有无锌手指,最早是在人类NEIL1中描述的,而不是Fpg / Nei家族中常见的标志性锌手指。与大肠杆菌Nei相反,后者在结合DNA时观察到巨大的构象变化,与DNA结合的MvNei1的结构与未结合的酶相比没有任何实质性的移动。包含MvNei1中217-245位残基的蛋白质片段对应于大肠杆菌Nei中的“缺失环”和大肠杆菌Fpg中的“αF-β10环”,据报道这与病变识别有关。有趣的是,与其他Fpg / Nei酶不同,MvNei1中相应的环在未配体和呋喃结合的结构中都是有序的,而在其他Fpg / Nei酶中,环通常在未配体的酶中或与病变复合体中排列,否则混乱。在MvNei1·四氢呋喃复合物中,位于假定病灶识别环末端的酪氨酸紧贴呋喃环。酪氨酸预计将采用不同的构象以适应修饰的碱基。

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