9OPR

TMPRSS2 S441A in complex with the H1H7 Fab and anti-kappa light chain nanobody

Summary for 9OPR

• Entry DOI: 10.2210/pdb9opr/pdb
• EMDB information: 70722
• Descriptor: Transmembrane protease serine 2, H1H7 antibody heavy chain, H1H7 antibody light chain, ... (6 entities in total)
• Functional Keywords: h1h7, nanobody, antibody, tmprss2, nl63, hku1, rbd, s2prime, coronavirus, cleavage, sars-cov-2, spike, fusion, protease, entry, antiviral, structural genomics, seattle structural genomics center for infectious disease, ssgcid, hydrolase-immune system complex, hydrolase/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 124118.69

Authors

McCallum, M.,Seattle Structural Genomics Center for Infectious Disease (SSGCID),Veesler, D. (deposition date: 2025-05-19, release date: 2026-05-13)

Primary citation

McCallum, M.,Case, J.B.,Brown, J.T.,Park, Y.J.,Lee, J.,Sutherland, E.,Aggarwal, A.,Gibson, C.,Lempp, F.A.,Stewart, C.,Tortorici, M.A.,Sanapala, S.,Low, J.S.,Asarnow, D.,Bohan, D.,Dellota Jr., E.,Merz, B.,Chawla, B.,Kar, S.,Lanzavecchia, A.,Sallusto, F.,Riley, N.M.,Turville, S.,Purcell, L.,Diamond, M.S.,Veesler, D.
TMPRSS2-mediated coronavirus spike activation and inhibition.
Nat.Struct.Mol.Biol., 2026

PubMed Abstract: The 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' site and promotes fusogenic conformational changes leading to viral entry. We unveil TMPRSS2 recognition of S', identify key residues modulating binding specificity and demonstrate that S' 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' site-directed antibodies in coronavirus entry.

PubMed: 42050172
DOI: 10.1038/s41594-026-01801-y

Experimental method

ELECTRON MICROSCOPY (3.2 Å)