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Title | Human coronavirus HKU1 recognition of the TMPRSS2 host receptor. |
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Journal, issue, pages | Cell, Vol. 187, Issue 16, Page 4231-4245.e13, Year 2024 |
Publish date | Aug 8, 2024 |
![]() | Matthew McCallum / Young-Jun Park / Cameron Stewart / Kaitlin R Sprouse / Amin Addetia / Jack Brown / M Alejandra Tortorici / Cecily Gibson / Emily Wong / Margareta Ieven / Amalio Telenti / David Veesler / ![]() ![]() |
PubMed Abstract | 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 ...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. |
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Methods | EM (single particle) |
Resolution | 2.9 Å |
Structure data | EMDB-43224, PDB-8vgt: |
Chemicals | ![]() ChemComp-NAG: |
Source |
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![]() | VIRAL PROTEIN / Spike glycoprotein / fusion protein / Structural Genomics / Seattle Structural Genomics Center for Infectious Disease / SSGCID / inhibitor |