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TMPRSS2 and glycan receptors synergistically facilitate coronavirus entry

Affiliations
  • 1Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China.
  • 2Shanghai Fifth People’s Hospital, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Key Laboratory of Medical Epigenetics and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
  • 3The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
  • 4Guangzhou Laboratory, Guangzhou 510005, China.
  • 5Key Laboratory of Marine Drugs of Ministry of Education, Shandong Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
  • 6School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia.

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July 4, 2024

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.

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