8DI5

Cryo-EM structure of SARS-CoV-2 Beta (B.1.351) spike protein in complex with VH domain F6 (focused refinement of RBD and VH F6)

Summary for 8DI5

• Entry DOI: 10.2210/pdb8di5/pdb
• EMDB information: 27438 27439
• Descriptor: Spike glycoprotein, VH F6, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: sars-cov-2, glycoprotein, fusion protein, viral protein, vh domain, f6, viral protein-immune system complex, viral protein/immune system
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 2
• Total formula weight: 155653.10

Authors

Zhu, X.,Saville, J.W.,Mannar, D.,Berezuk, A.M.,Subramaniam, S. (deposition date: 2022-06-28, release date: 2022-08-24, Last modification date: 2024-10-09)

Primary citation

Chen, C.,Saville, J.W.,Marti, M.M.,Schafer, A.,Cheng, M.H.,Mannar, D.,Zhu, X.,Berezuk, A.M.,Banerjee, A.,Sobolewski, M.D.,Kim, A.,Treat, B.R.,Da Silva Castanha, P.M.,Enick, N.,McCormick, K.D.,Liu, X.,Adams, C.,Hines, M.G.,Sun, Z.,Chen, W.,Jacobs, J.L.,Barratt-Boyes, S.M.,Mellors, J.W.,Baric, R.S.,Bahar, I.,Dimitrov, D.S.,Subramaniam, S.,Martinez, D.R.,Li, W.
Potent and broad neutralization of SARS-CoV-2 variants of concern (VOCs) including omicron sub-lineages BA.1 and BA.2 by biparatopic human VH domains.
Iscience, 25:104798-104798, 2022

PubMed Abstract: The emergence of SARS-CoV-2 variants of concern (VOCs) requires the development of next-generation biologics with high neutralization breadth. Here, we characterized a human V domain, F6, which we generated by sequentially panning large phage-displayed V libraries against receptor binding domains (RBDs) containing VOC mutations. Cryo-EM analyses reveal that F6 has a unique binding mode that spans a broad surface of the RBD and involves the antibody framework region. Attachment of an Fc region to a fusion of F6 and ab8, a previously characterized V domain, resulted in a construct (F6-ab8-Fc) that broadly and potently neutralized VOCs including Omicron. Additionally, prophylactic treatment using F6-ab8-Fc reduced live Beta (B.1.351) variant viral titers in the lungs of a mouse model. Our results provide a new potential therapeutic against SARS-CoV-2 variants including Omicron and highlight a vulnerable epitope within the spike that may be exploited to achieve broad protection against circulating variants.

PubMed: 35875685
DOI: 10.1016/j.isci.2022.104798

Experimental method

ELECTRON MICROSCOPY (3.04 Å)