8DV2

SARS-CoV-2 Wuhan-hu-1-Spike-RBD bound to computationally engineered ACE2 mimetic CVD293

Summary for 8DV2

• Entry DOI: 10.2210/pdb8dv2/pdb
• EMDB information: 27731
• Descriptor: Spike glycoprotein, Angiotensin-converting enzyme 2,Immunoglobulin gamma-1 heavy chain fusion, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: sars-cov-2, spike, receptor-binding domain, ace2 receptor traps, antiviral protein, viral protein-antiviral protein complex, viral protein/antiviral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 2
• Total formula weight: 249170.96

Authors

QCRG Structural Biology Consortium,Remesh, S.G.,Merz, G.E.,Brilot, A.F.,Chio, U.,Verba, K.A. (deposition date: 2022-07-27, release date: 2022-08-31, Last modification date: 2024-10-30)

Primary citation

Remesh, S.G.,Merz, G.E.,Brilot, A.F.,Chio, U.S.,Rizo, A.N.,Pospiech Jr., T.H.,Lui, I.,Laurie, M.T.,Glasgow, J.,Le, C.Q.,Zhang, Y.,Diwanji, D.,Hernandez, E.,Lopez, J.,Mehmood, H.,Pawar, K.I.,Pourmal, S.,Smith, A.M.,Zhou, F.,DeRisi, J.,Kortemme, T.,Rosenberg, O.S.,Glasgow, A.,Leung, K.K.,Wells, J.A.,Verba, K.A.
Computational pipeline provides mechanistic understanding of Omicron variant of concern neutralizing engineered ACE2 receptor traps.
Structure, 31:253-, 2023

PubMed Abstract: The SARS-CoV-2 Omicron variant, with 15 mutations in Spike receptor-binding domain (Spike-RBD), renders virtually all clinical monoclonal antibodies against WT SARS-CoV-2 ineffective. We recently engineered the SARS-CoV-2 host entry receptor, ACE2, to tightly bind WT-RBD and prevent viral entry into host cells ("receptor traps"). Here we determine cryo-EM structures of our receptor traps in complex with stabilized Spike ectodomain. We develop a multi-model pipeline combining Rosetta protein modeling software and cryo-EM to allow interface energy calculations even at limited resolution and identify interface side chains that allow for high-affinity interactions between our ACE2 receptor traps and Spike-RBD. Our structural analysis provides a mechanistic rationale for the high-affinity (0.53-4.2 nM) binding of our ACE2 receptor traps to Omicron-RBD confirmed with biolayer interferometry measurements. Finally, we show that ACE2 receptor traps potently neutralize Omicron and Delta pseudotyped viruses, providing alternative therapeutic routes to combat this evolving virus.

PubMed: 36805129
DOI: 10.1016/j.str.2023.01.009

Experimental method

ELECTRON MICROSCOPY (3.5 Å)