9DGO

Designed miniproteins potently inhibit and protect against MERS-CoV. Crystal structure of MERS-CoV S RBD in complex with miniprotein cb3

Summary for 9DGO

• Entry DOI: 10.2210/pdb9dgo/pdb
• Related: 9DKK
• Descriptor: Spike glycoprotein, Designed miniprotein cb_3, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: mers-cov, miniproteins, neutralization, fusion, cryo-em, biolayer interferometry, mers-cov strains, structural genomics, seattle structural genomics center for infectious disease, ssgcid, viral protein
• Biological source: Middle East respiratory syndrome-related coronavirus; More
• Total number of polymer chains: 4
• Total formula weight: 71620.58

Authors

Tortorici, M.A.,Veesler, D.,Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2024-09-03, release date: 2025-06-18)

Primary citation

Ragotte, R.J.,Tortorici, M.A.,Catanzaro, N.J.,Addetia, A.,Coventry, B.,Froggatt, H.M.,Lee, J.,Stewart, C.,Brown, J.T.,Goreshnik, I.,Sims, J.N.,Milles, L.F.,Wicky, B.I.M.,Glogl, M.,Gerben, S.,Kang, A.,Bera, A.K.,Sharkey, W.,Schafer, A.,Harkema, J.R.,Baric, R.S.,Baker, D.,Veesler, D.
Designed miniproteins potently inhibit and protect against MERS-CoV.
Cell Rep, 44:115760-115760, 2025

PubMed Abstract: Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic pathogen with a 36% case-fatality rate in humans. No vaccines or specific therapeutics are currently approved for use in humans or the camel host reservoir. Here, we computationally designed monomeric and homo-oligomeric miniproteins that bind with high affinity to the MERS-CoV spike (S) glycoprotein, the main target of neutralizing antibodies and vaccine development. We show that these miniproteins broadly neutralize a panel of MERS-CoV S variants, spanning the known antigenic diversity of this pathogen, by targeting a conserved site in the receptor-binding domain (RBD). The miniproteins directly compete with binding of the dipeptidylpeptidase 4 (DPP4) receptor to MERS-CoV S, thereby blocking viral attachment to the host entry receptor and subsequent membrane fusion. Intranasal administration of a lead miniprotein provides prophylactic protection against stringent MERS-CoV challenge in mice, motivating its future clinical development as a next-generation countermeasure against this virus with pandemic potential.

PubMed: 40450691
DOI: 10.1016/j.celrep.2025.115760

Experimental method

X-RAY DIFFRACTION (1.85 Å)