9z3j | pdb_00009z3j
HCoV-NL63 S2' peptide bound to TMPRSS2 S441A (complexed with the H1H7 Fab and an anti-kappa-nanobody)
Structural highlights
FunctionSPIKE_CVHNL S1 region attaches the virion to the cell membrane by interacting with human ACE2, initiating the infection. Binding to the receptor probably induces conformational changes in the S glycoprotein unmasking the fusion peptide of S2 region and activating membranes fusion. S2 region belongs to the 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) regions 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 (By similarity). Publication Abstract from PubMedThe protease TMPRSS2 facilitates coronavirus infections, yet its mechanism of viral glycoprotein recognition remains unclear. Here we show that, following ACE2 engagement of the SARS-CoV-2 spike (S) inducing the early fusion intermediate conformation (E-FIC), TMPRSS2 cleaves the R815 S(2)' site and promotes fusogenic conformational changes leading to viral entry. We unveil TMPRSS2 recognition of S(2)', identify key residues modulating binding specificity and demonstrate that S(2)' site-directed broadly neutralizing antibodies target E-FIC and inhibit viral entry by blocking TMPRSS2 access. We computationally designed stabilized E-FIC as a vaccine candidate, overcoming the transient nature of this state. We describe a TMPRSS2-directed monoclonal antibody inhibiting several coronaviruses, including SARS-CoV-2 variants and protecting mice against SARS-CoV-2 challenge. These results outline the mechanistic role of TMPRSS2 and S(2)' site-directed antibodies in coronavirus entry. TMPRSS2-mediated coronavirus spike activation and inhibition.,McCallum M, Case JB, Brown JT, Park YJ, Lee J, Sutherland E, Aggarwal A, Gibson C, Lempp FA, Stewart C, Tortorici MA, Sanapala S, Low JS, Asarnow D, Bohan D, Dellota E Jr, Merz B, Chawla B, Kar S, Lanzavecchia A, Sallusto F, Riley NM, Turville S, Purcell L, Diamond MS, Veesler D Nat Struct Mol Biol. 2026 Apr 28. doi: 10.1038/s41594-026-01801-y. PMID:42050172[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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