Structural basis for the interaction between human coronavirus HKU1 spike receptor binding domain and its receptor TMPRSS2

HKU1 coronavirus (CoV) infection can be severe in children, elderly, or immunocompromised patients 1 . As a member of the Embecovirus , HKU1 uses a primary glycan-based receptor (9- O -acetylated sialosides) and a secondary proteinaceous receptor for host cell targeting and membrane fusion 2 , 3 . One unique feature of HKU1 spike is that the C-terminal domain (CTD) of S1 (also known as receptor-binding domain, RBD) is exceptionally larger than other CoV RBDs, and the receptor-binding motif (RBM) of HKU1 adopts a unique fold 4 . A recent cryogenic electron microscopy (Cryo-EM) study revealed that binding of a 9- O -acetylated α2,8-linked sialic acid to the HUK1 spike S1-NTD leads to an allosteric switching of the adjacent RBD to “up” conformation, thereby allowing secondary receptor binding 3 . Proteinaceous receptor of HKU1 was identified as transmembrane serine protease 2 (TMPRSS2) and HKU1 RBD binds TMPRSS2 with nanomolar affinity 2 . Nevertheless, detailed mapping of the interaction between HKU1 spike and TMPRSS2 remains unavailable.