Crystal structure of 2C helicase from enterovirus 71.
Crystal structure of 2C helicase from enterovirus 71.
复制标题
肠道病毒 71 的 2C 解旋酶的晶体结构。
DOI：
10.1126/sciadv.1602573
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发表时间：
2017-04
期刊：
影响因子：
13.6
通讯作者：
Cui S
中科院分区：
文献类型：
--
作者：
Guan H;Tian J;Qin B;Wojdyla JA;Wang B;Zhao Z;Wang M;Cui S
EV 71 2C的结构揭示了羧基末端介导的自身寡聚化的功能机制的结构基础。肠道病毒71型（EV 71）是引起手足口病暴发的主要病原体。EV 71非结构蛋白2C参与了整个病毒生命周期中的许多关键事件;然而，其确切作用尚未完全了解。缺乏高分辨率的结构使得难以阐明2C活性并阻止抑制剂的产生。我们报告了EV 71 2C可溶性部分的2.5 nm分辨率晶体结构，包含一个腺苷三磷酸酶（ATP酶）结构域，一个富含半胱氨酸的具有不寻常折叠的锌指结构域和一个羧基末端螺旋结构域。与其他AAA+ ATP酶不同，EV 71 2C经历羧基末端介导的自身寡聚化，这依赖于一个单体的羧基末端螺旋与ATP酶和相邻单体的锌指结构域之间形成的深口袋之间的特异性相互作用。羧基端介导的自身寡聚化是2C ATP酶活性和EV 71复制的基础。我们的研究结果表明，通过破坏2C的自寡聚化界面来抑制肠道病毒复制的策略。
Structure of EV71 2C unveils the structural basis of the functional mechanism of carboxyl terminus–mediated self-oligomerization. Enterovirus 71 (EV71) is the major pathogen responsible for outbreaks of hand, foot, and mouth disease. EV71 nonstructural protein 2C participates in many critical events throughout the virus life cycle; however, its precise role is not fully understood. Lack of a high-resolution structure made it difficult to elucidate 2C activity and prevented inhibitor development. We report the 2.5 Å–resolution crystal structure of the soluble part of EV71 2C, containing an adenosine triphosphatase (ATPase) domain, a cysteine-rich zinc finger with an unusual fold, and a carboxyl-terminal helical domain. Unlike other AAA+ ATPases, EV71 2C undergoes a carboxyl terminus–mediated self-oligomerization, which is dependent on a specific interaction between the carboxyl-terminal helix of one monomer and a deep pocket formed between the ATPase and the zinc finger domains of the neighboring monomer. The carboxyl terminus–mediated self-oligomerization is fundamental to 2C ATPase activity and EV71 replication. Our findings suggest a strategy for inhibition of enterovirus replication by disruption of the self-oligomerization interface of 2C.