%0 Journal Article
%T Human coronavirus HKU1 recognition of the TMPRSS2 host receptor.
%A McCallum M
%A Park YJ
%A Stewart C
%A Sprouse KR
%A Addetia A
%A Brown J
%A Tortorici MA
%A Gibson C
%A Wong E
%A Ieven M
%A Telenti A
%A Veesler D
%J Cell
%V 0
%N 0
%D 2024 Jun 26
%M 38964328
%F 66.85
%R 10.1016/j.cell.2024.06.006
%X 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.