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TitleStructural characterization of human monoclonal antibodies targeting uncommon antigenic sites on spike glycoprotein of SARS-CoV.
Journal, issue, pagesJ Clin Invest, Vol. 135, Issue 3, Year 2024
Publish dateNov 26, 2024
AuthorsNaveenchandra Suryadevara / Nurgun Kose / Sandhya Bangaru / Elad Binshtein / Jennifer Munt / David R Martinez / Alexandra Schäfer / Luke Myers / Trevor D Scobey / Robert H Carnahan / Andrew B Ward / Ralph S Baric / James E Crowe /
PubMed AbstractThe function of the spike protein N terminal domain (NTD) in coronavirus (CoV) infections is poorly understood. However, some rare antibodies that target the SARS-CoV-2 NTD potently neutralize the ...The function of the spike protein N terminal domain (NTD) in coronavirus (CoV) infections is poorly understood. However, some rare antibodies that target the SARS-CoV-2 NTD potently neutralize the virus. This finding suggests the NTD may contribute, in part, to protective immunity. Pansarbecovirus antibodies are desirable for broad protection, but the NTD region of SARS-CoV and SARS-CoV-2 exhibit a high level of sequence divergence; therefore, cross-reactive NTD-specific antibodies are unexpected, and there is no structure of a SARS-CoV NTD-specific antibody in complex with NTD. Here, we report a monoclonal antibody COV1-65, encoded by the IGHV1-69 gene, that recognizes the NTD of SARS-CoV S protein. A prophylaxis study showed the mAb COV1-65 prevented disease when administered before SARS-CoV challenge of BALB/c mice, an effect that requires intact fragment crystallizable region (Fc) effector functions for optimal protection in vivo. The footprint on the S protein of COV1-65 is near to functional components of the S2 fusion machinery, and the selection of COV1-65 escape mutant viruses identified critical residues Y886H and Q974H, which likely affect the epitope through allosteric effects. Structural features of the mAb COV1-65-SARS-CoV antigen interaction suggest critical antigenic determinants that should be considered in the rational design of sarbecovirus vaccine candidates.
External linksJ Clin Invest / PubMed:39589795 / PubMed Central
MethodsEM (single particle)
Resolution3.2 - 4.5 Å
Structure data

EMDB-43407, PDB-8vpf:
Structure of SARS-CoV spike in complex with CoV1-65 Fab (NTD-bound)
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-43408: Structure of SARS-CoV spike in complex with CoV1-62 IgG
Method: EM (single particle) / Resolution: 4.5 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • Human coronavirus OC43
  • severe acute respiratory syndrome coronavirus
  • homo sapiens (human)
  • SARS coronavirus Urbani
KeywordsVIRAL PROTEIN / SARS-CoV / Spike / Monoclonal antibody / Complex / NTD

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