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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structure Of Coronavirus Hemagglutinin-esterase Offers Insight Into Corona And Influenza Virus Evolution
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Structure Of Coronavirus Hemagglutinin-esterase Offers Insight Into Corona And Influenza Virus Evolution

机译：冠状病毒血凝素酯酶的结构可深入了解冠状病毒和流感病毒的进化

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摘要

The hemagglutinin-esterases (HEs) are a family of viral envelope glycoproteins that mediate reversible attachment to O-acetylated sialic acids by acting both as lectins and as receptor-destroying enzymes (RDEs). Related HEs occur in influenza C, toro-, and coronaviruses, apparently as a result of relatively recent lateral gene transfer events. Here, we report the crystal structure of a coronavirus (CoV) HE in complex with its receptor. We show that CoV HE arose from an influenza C-like HE fusion protein (HEF). In the process, HE was transformed from a trimer into a dimer, whereas remnants of the fusion domain were adapted to establish novel monomer-monomer contacts. Whereas the structural design of the RDE-acetylesterase domain remained unaltered, the HE receptor-binding domain underwent remodeling to such extent that the ligand is now bound in opposite orientation. This is surprising, because the architecture of the HEF site was preserved in influenza A HA over a much larger evolutionary distance, a switch in receptor specificity and extensive antigenic variation notwithstanding. Apparently, HA and HEF are under more stringent selective constraints than HE, limiting their exploration of alternative binding-site topologies. We attribute the plasticity of the CoV HE receptor-binding site to evolutionary flexibility conferred by functional redundancy between HE and its companion spike protein S. Our findings offer unique insights into the structural and functional consequences of independent protein evolution after interviral gene exchange and open potential avenues to broad-spectrum antiviral drug design.
机译：血凝素酯酶（HEs）是一类病毒被膜糖蛋白，通过充当凝集素和破坏受体的酶（RDE）来介导与O-乙酰化唾液酸的可逆连接。相关的HEs发生在丙型流感病毒，弓形病毒和冠状病毒中，这显然是相对近期的横向基因转移事件的结果。在这里，我们报告冠状病毒（CoV）HE与其受体复合的晶体结构。我们显示，冠状病毒HE源自C型流感HE融合蛋白（HEF）。在此过程中，HE从三聚体转变为二聚体，而融合结构域的残基则适于建立新型单体-单体接触。尽管RDE-乙酰酯酶结构域的结构设计没有改变，但是HE受体结合结构域进行了重塑，使得配体现在以相反的方向结合。这是令人惊奇的，因为HEF位点的结构在A型流感HA中保留了更大的进化距离，尽管受体特异性发生了变化并且抗原变化广泛。显然，HA和HEF比HE受到更严格的选择约束，从而限制了他们对替代结合位点拓扑结构的探索。我们将CoV HE受体结合位点的可塑性归因于HE及其伴随的刺突蛋白S之间的功能冗余所赋予的进化灵活性。我们的发现为病毒间基因交换和开放潜力后独立蛋白进化的结构和功能后果提供了独特见解广谱抗病毒药物设计的途径。

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