Structural basis of staphylococcal Stl inhibition on a eukaryotic dUTPase
Structural basis of staphylococcal Stl inhibition on a eukaryotic dUTPase
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葡萄球菌 Stl 抑制真核 dUTP 酶的结构基础
DOI：
10.1016/j.ijbiomac.2021.06.107
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发表时间：
2021-06-28
影响因子：
8.2
通讯作者：
Ma, Qingjun
中科院分区：
文献类型：
--
作者：
Wang, Fang;Liu, Changshui;Ma, Qingjun
Dutpases是所有生活王国中的关键酶。葡萄球菌抑制剂蛋白（STL）抑制了多种物种到各种扩展的DUTPass。了解抑制差异的分子基础对于发展有效的dutpass抑制剂至关重要。在此，我们报告了Stl N末端结构域（Stln-Ter）和Litopenaeus Vannamei Dutpase域（LVDUT65-210）的复杂结构。 STL通过其N末端结构域抑制LVDUT65-210。 LVDUT65-210-STLN-TER复合结构揭示了一个杂己，包含三个与一个LVDUT65-210夹子结合的STLN-TER单体，生成了两种类型的STL-DUTPase接口。接口I是通过与LVDUT65-210活跃位点的STL相互作用形成的，该区域由基序I-IV从其两个亚基中贡献。 II界面II是由于第三LVDUT65-210亚基与C末端基序V的STL结合而产生的。结构比较揭示了STL-DUTPase相互作用模式的保守特征和明显的差异，从而提供了有关STL对DUTPases的抑制差异的线索。明显的是，仅在LVDUT65-210-STLN-TER中观察到II接口II。 LVDUT65-210的STL相互作用残基在其他真核Dutpass中保守，尤其是人类DUTPase。总的来说，我们的研究介绍了与真核杜帕酶相互作用的第一个结构模型，这有助于对STL抑制作用进行更完整的视野，并促进蛋白质抑制剂对真核荷培酶的发展。
dUTPases are key enzymes in all life kingdoms. A staphylococcal repressor protein (Stl) inhibited dUTPases from multiple species to various extents. Understanding the molecular basis underlying the inhibition differences is crucial to develop effective proteinaceous inhibitors of dUTPases. Herein, we report the complex structure of Stl N-terminal domain (StlN-ter) and Litopenaeus vannamei dUTPase domain (lvDUT65-210). Stl inhibited lvDUT65-210 through its N-terminal domain. The lvDUT65-210-StlN-ter complex structure revealed a heterohexamer encompassing three StlN-ter monomers bound to one lvDUT65-210 trimer, generating two types of Stl-dUTPase interfaces. Interface I is formed by Stl interaction with the lvDUT65-210 active-site region that is contributed by motifs I-IV from its two subunits; interface II results from Stl binding to the C-terminal motif V of the third lvDUT65-210 subunit. Structural comparison revealed both conserved features and obvious differences in Stl-dUTPase interaction patterns, giving clues about the inhibition differences of Stl on dUTPases. Noticeably, interface II is only observed in lvDUT65-210-StlN-ter. The Stl-interacting residues of lvDUT65-210 are conserved in other eukaryotic dUTPases, particularly human dUTPase. Altogether, our study presents the first structural model of Stl interaction with eukaryotic dUTPase, contributing to a more complete view of Stl inhibition and facilitating the development of proteinaceous inhibitor for eukaryotic dUTPases.