An Open Receptor-Binding Cavity of Hemagglutinin-Esterase-Fusion Glycoprotein from Newly-Identified Influenza D Virus: Basis for Its Broad Cell Tropism.
An Open Receptor-Binding Cavity of Hemagglutinin-Esterase-Fusion Glycoprotein from Newly-Identified Influenza D Virus: Basis for Its Broad Cell Tropism.
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DOI：
10.1371/journal.ppat.1005411
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发表时间：
2016-01
期刊：
影响因子：
6.7
通讯作者：
Gao GF
中科院分区：
文献类型：
--
作者：
Song H;Qi J;Khedri Z;Diaz S;Yu H;Chen X;Varki A;Shi Y;Gao GF
流感病毒每年引起季节性流感，偶尔引起大流行或流行病，对公众健康构成重大威胁。最近，从猪和牛中分离出一种新的D型流感病毒。在这里，我们发现IDV利用9- o乙酰化唾液酸作为病毒进入的受体。然后，我们确定了IDV血凝素-酯酶融合糖蛋白（HEF）的晶体结构，包括其自由形态和与受体和酶底物类似物的复合物。IDV HEF表现出与人感染的C型流感病毒（ICV） HEF极其相似的结构折叠。然而，IDV HEF有一个开放的受体结合腔，以容纳各种延长的聚糖片段。这种结构上的差异解释了IDV具有广泛的细胞向性的现象。由于IDV HEF在结构和功能上与ICV HEF相似，我们的研究结果强调了该病毒对公共卫生的潜在威胁。在正粘病毒科病毒中，甲型、乙型和丙型流感病毒都可引起人类疾病。最近，在猪和牛中发现了一种新型D型流感病毒（IDV），其氨基酸与人类C型流感病毒（ICV）的相似性约为50%。这种新型病毒可以在包括雪貂和豚鼠在内的其他哺乳动物中建立感染。然而，病毒进入的细胞受体及其广泛宿主范围的分子机制尚不清楚。我们对病毒表面蛋白血凝素-酯酶融合（HEF）进行了结构和功能研究，并证明IDV（与ICV一样）使用9- o乙酰化唾液酸作为其受体，但IDV HEF具有开放的受体结合腔以容纳各种扩展的聚糖片段。我们的研究结果非常详细地揭示了受体或底物如何结合到受体结合位点或酯酶活性位点，为开发针对保守酯酶袋的新疗法提供了线索。此外，IDV HEF可以结合人气管上皮，这表明IDV病毒可能成为对公众健康的潜在威胁。
Influenza viruses cause seasonal flu each year and pandemics or epidemic sporadically, posing a major threat to public health. Recently, a new influenza D virus (IDV) was isolated from pigs and cattle. Here, we reveal that the IDV utilizes 9-O-acetylated sialic acids as its receptor for virus entry. Then, we determined the crystal structures of hemagglutinin-esterase-fusion glycoprotein (HEF) of IDV both in its free form and in complex with the receptor and enzymatic substrate analogs. The IDV HEF shows an extremely similar structural fold as the human-infecting influenza C virus (ICV) HEF. However, IDV HEF has an open receptor-binding cavity to accommodate diverse extended glycan moieties. This structural difference provides an explanation for the phenomenon that the IDV has a broad cell tropism. As IDV HEF is structurally and functionally similar to ICV HEF, our findings highlight the potential threat of the virus to public health. Of the Orthomyxoviridae family of viruses, influenza A, B and C viruses all can cause disease in humans. Recently, a novel influenza D virus (IDV) with approximately 50% amino acid identity to human influenza C virus (ICV) is found in pigs and cattle. This novel virus can establish infection in other mammals including ferrets and guinea pigs. However, the cellular receptor for viral entry and the molecular mechanism for its broad host range is unclear. We performed combined structural and functional studies on the viral surface protein, hemagglutinin-esterase-fusion (HEF), and demonstrated that IDV (like ICV) uses 9-O-acetylated sialic acid as its receptor, but the IDV HEF has an open receptor-binding cavity to accommodate diverse extended glycan moieties. Our findings reveal in exquisite detail how the receptors or substrates bind to the receptor-binding site or esterase active site, providing a clue for the development of novel therapeutics against the conserved esterase pocket. Furthermore, the IDV HEF can bind human trachea epithelia, indicating that the IDV virus may become a potential threat to public health.