9opq
TMPRSS2 (S441A) bound to the HCoV-NL63 S2'region genetically fused to the HCoV-HKU1 RBD
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 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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