8vgt
Structure of the HKU1 RBD bound to the human TMPRSS2 receptor
Structural highlights
FunctionSPIKE_CVHN1 S1 attaches the virion to the cell membrane by interacting with cell receptors, initiating the infection. S2 is a class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes. Presumably interacts with target cell lipid raft after cell attachment (By similarity). Publication Abstract from PubMedThe 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. Human coronavirus HKU1 recognition of the TMPRSS2 host receptor.,McCallum M, Park YJ, Stewart C, Sprouse KR, Addetia A, Brown J, Tortorici MA, Gibson C, Wong E, Ieven M, Telenti A, Veesler D Cell. 2024 Jun 26:S0092-8674(24)00646-9. doi: 10.1016/j.cell.2024.06.006. PMID:38964328[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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