Abstract：
The entry of coronaviruses is initiated by spike recognition of host cellular receptors, involving proteinaceous and/or glycan receptors. Recently, TMPRSS2 was identified as the proteinaceous receptor for HCoV-HKU1 alongside sialoglycan as a glycan receptor. However, the underlying mechanisms for viral entry remain unknown. Here, we investigated the HCoV-HKU1C spike in the inactive, glycan-activated, and functionally anchored states, revealing that sialoglycan binding induces a conformational change of the NTD and promotes the neighboring RBD of the spike to open for TMPRSS2 recognition, exhibiting a synergistic mechanism for the entry of HCoV-HKU1. The RBD of HCoV-HKU1 features an insertion subdomain that recognizes TMPRSS2 through three previously undiscovered interfaces. Furthermore, structural investigation of HCoV-HKU1A in combination with mutagenesis and binding assays confirms a conserved receptor recognition pattern adopted by HCoV-HKU1. These studies advance our understanding of the complex viral-host interactions during entry, laying the groundwork for developing new therapeutics against coronavirus-associated diseases.
摘要：
冠状病毒的进入是由宿主细胞受体的尖峰识别启动的，涉及蛋白质和/或聚糖受体。最近,TMPRSS2被鉴定为HCoV-HKU1的蛋白质受体，与唾液酸聚糖作为聚糖受体一起。然而,病毒进入的潜在机制仍然未知.这里,我们调查了不活跃的HCoV-HKU1C峰值，聚糖激活，和功能锚定状态，揭示唾液酸聚糖结合诱导NTD的构象变化，并促进尖峰的相邻RBD打开以识别TMPRSS2，表现出HCoV-HKU1进入的协同机制。HCoV-HKU1的RBD具有通过三个先前未发现的接口识别TMPRSS2的插入子域。此外，HCoV-HKU1A的结构研究与诱变和结合测定相结合，证实了HCoV-HKU1采用的保守受体识别模式。这些研究促进了我们对进入过程中复杂的病毒与宿主相互作用的理解，为开发针对冠状病毒相关疾病的新疗法奠定基础。
