作者
Haofeng Wang,Xiaoce Liu,Xiang Zhang,Zhuoqian Zhao,Yuchi Lu,Dan Pu,Zeyang Zhang,Jie Chen,Yajie Wang,Mengfei Li,Haitao Yang,Ying Duan,Yujia He,Qiyu Mao,Hangtian Guo,Haoran Sun,Yi-Han Zhou,Qi Yang,Yan Gao,Haitao Yang,Hongzhi Cao,Luke W. Guddat,Lei Sun,Zihe Rao,Haitao Yang
摘要
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.