National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
AI158186
米国
引用
ジャーナル: Cell / 年: 2024 タイトル: Human coronavirus HKU1 recognition of the TMPRSS2 host receptor. 著者: 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 / 要旨: 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.