Human coronavirus HKU1 recognition of the TMPRSS2 host receptor
- Cell. 2024 Aug 8;187(16):4231-4245.e13. doi: 10.1016/j.cell.2024.06.006.
- 1. Department of Biochemistry, University of Washington, Seattle, WA, USA.
- 2. Department of Biochemistry, University of Washington, Seattle, WA, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA.
- 3. Vir Biotechnology, San Francisco, CA 94158, USA.
- 4. Laboratory of Clinical Microbiology, Vaccine & Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
- 5. Department of Biochemistry, University of Washington, Seattle, WA, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA. Electronic address: [email protected].
The human coronavirus HKU1 spike (S) glycoprotein engages host cell surface sialoglycans and transmembrane Protease serine 2 (TMPRSS2) to initiate Infection. The molecular basis of HKU1 binding to TMPRSS2 and determinants of host receptor tropism remain elusive. We designed an active human TMPRSS2 construct enabling high-yield Recombinant production in human cells of this key therapeutic target. We determined a cryo-electron microscopy structure of the HKU1 RBD bound to human TMPRSS2, providing a blueprint of the interactions supporting viral entry and explaining the specificity for TMPRSS2 among orthologous proteases. We identified TMPRSS2 orthologs from five mammalian orders promoting HKU1 S-mediated entry into cells along with key residues governing host receptor usage. Our data show that the TMPRSS2 binding motif is a site of vulnerability to neutralizing antibodies and suggest that HKU1 uses S conformational masking and glycan shielding to balance immune evasion and receptor engagement.