Crystal structure of a soluble fragment of poliovirus 2CATPase.
Crystal structure of a soluble fragment of poliovirus 2CATPase.
复制标题
脊髓灰质炎病毒 2CATP 酶可溶性片段的晶体结构。
DOI：
10.1371/journal.ppat.1007304
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发表时间：
2018-09
期刊：
影响因子：
6.7
通讯作者：
Cui S
中科院分区：
文献类型：
--
作者：
Guan H;Tian J;Zhang C;Qin B;Cui S
脊髓灰质炎病毒(PV)2CATP酶是目前研究最多的一种脊髓灰质炎病毒(PV)2C蛋白。它参与了RNA的复制、包被和去包被，并发现了许多靶向PV2CATPase的抑制剂。尽管对其功能进行了大量研究，但尚未确定PV 2C的高分辨率结构。本文报道了PV2CATPase可溶片段的晶体结构，该片段含有一个ATPase结构域、一个锌指和一个C-末端螺旋结构域，但没有N-末端结构域。ATPase结构域与EV71 2C和其他超家族3解旋酶具有共同的结构特征。C-末端富含半胱氨酸的基序折叠成CCCC类型的锌指，其中四个半胱氨酸配体和几个辅助残基协助锌结合。通过与已知的锌指折叠基团的比较，我们发现2C蛋白的锌指属于一个新的折叠基团，我们称之为肠道病毒2C样折叠基团。PV2CATPase的C末端形成一个两亲性螺旋，占据位于晶格中相邻PV2CATPase上的疏水口袋。C末端介导的PV 2C-2C相互作用促进自身寡聚，最有可能的是六聚化，这是2C ATPase活性的基础。锌指是2C蛋白中结构最多样化的特征。现有的结构和病毒学数据表明，2C的锌指可能具有与其他蛋白质相互作用的特异性。我们构建了PV2CATPase的六聚体环模型，并可视化了先前发现的功能基序和耐药部位，从而为抗病毒药物的开发提供了一个结构框架。自发起全球根除脊髓灰质炎倡议以来，脊髓灰质炎病例数量大幅减少，但根除疾病的障碍依然存在。在结束阶段，抗脊髓灰质炎病毒药物将在控制疫苗衍生脊髓灰质炎病毒的传播和治疗慢性感染患者方面发挥关键作用。然而，目前还没有有效的抗脊髓灰质炎病毒药物可用。脊髓灰质炎病毒编码的2CATPase是最重要的药物靶点之一，已发现了许多2C的抑制剂。本文报道了PV2CATPase的可溶部分的晶体结构，该部分含有一个ATPase结构域、一个锌指和一个C-末端螺旋结构域。我们的发现不仅揭示了微小核糖核酸病毒2C蛋白家族的共同和个别结构特征，而且使我们能够可视化从数十年来对脊髓灰质炎病毒2CATPase的研究中发现的大量功能基序和耐药位点的集合。我们的发现对于理解微小核糖核酸病毒2C蛋白的功能和抗病毒药物的开发具有非常重要的价值。
Poliovirus (PV) 2CATPase is the most studied 2C protein in the Picornaviridae family. It is involved in RNA replication, encapsidation and uncoating and many inhibitors have been found that target PV 2CATPase. Despite numerous investigations to characterize its functions, a high-resolution structure of PV 2C has not yet been determined. We report here the crystal structure of a soluble fragment of PV 2CATPase to 2.55Å, containing an ATPase domain, a zinc finger and a C-terminal helical domain but missing the N-terminal domain. The ATPase domain shares the common structural features with EV71 2C and other Superfamily 3 helicases. The C-terminal cysteine-rich motif folds into a CCCC type zinc finger in which four cysteine ligands and several auxiliary residues assist in zinc binding. By comparing with the known zinc finger fold groups, we found the zinc finger of 2C proteins belong to a new fold group, which we denote the “Enterovirus 2C-like” group. The C-terminus of PV 2CATPase forms an amphipathic helix that occupies a hydrophobic pocket located on an adjacent PV 2CATPase in the crystal lattice. The C-terminus mediated PV 2C-2C interaction promotes self-oligomerization, most likely hexamerization, which is fundamental to the ATPase activity of 2C. The zinc finger is the most structurally diverse feature in 2C proteins. Available structural and virological data suggest that the zinc finger of 2C might confer the specificity of interaction with other proteins. We built a hexameric ring model of PV 2CATPase and visualized the previously identified functional motifs and drug-resistant sites, thus providing a structure framework for antiviral drug development. Since the launch of the Global Polio Eradication Initiative, the number of poliomyelitis cases has significantly reduced but obstacles to disease eradication remain. In the endgame phase, anti-poliovirus drugs will be critical in controlling transmission of vaccine-derived polioviruses and in treating patients with chronic infection. However, no effective anti-poliovirus drugs are yet available. The 2CATPase encoded by poliovirus is one of the most important drug targets, and many inhibitors of 2C have been found. We report here the crystal structure of a soluble portion of PV 2CATPase, containing an ATPase domain, a zinc finger and a C-terminal helical domain. Our findings not only revealed common and individual structural features in the picornaviral 2C protein family, but also allowed us to visualize a large collection of functional motifs and drug-resistant sites identified from the decades-long investigations of poliovirus 2CATPase. Our findings are invaluable for understanding the function of picornavirus 2C proteins and the development of antiviral drugs.
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影响因子：
5.4
作者：
Crotty, S;Saleh, MC;Andino, R
通讯作者：
Andino, R
影响因子：
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作者：
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影响因子：
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作者：
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DOI：
10.1006/bbrc.1995.1010
发表时间：
1995-01-05
影响因子：
3.1
作者：
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通讯作者：
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影响因子：
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作者：
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