9ECX

Crystal structure of the SARS-CoV-2 NTD-targeted neutralizing antibody WRAIR-2008

Summary for 9ECX

• Entry DOI: 10.2210/pdb9ecx/pdb
• Descriptor: WRAIR-2008 Fab heavy chain, WRAIR-2008 Fab light chain, GLYCEROL, ... (5 entities in total)
• Functional Keywords: antibody, neutralizing antibody, human antibody, sars-cov-2, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 4
• Total formula weight: 98139.32

Authors

Jensen, J.L.,Joyce, M.G. (deposition date: 2024-11-15, release date: 2025-08-20, Last modification date: 2025-10-22)

Primary citation

Dussupt, V.,Jensen, J.L.,Thomas, P.V.,Mendez-Rivera, L.,Lal, K.G.,Zemil McCrea, M.,Swafford, I.,Hernandez, J.,Sankhala, R.S.,Rao, M.,Arora, J.,Hajduczki, A.,Jian, N.,Rees, P.A.,Showell-De Leon, I.,Smith, G.,Smith, L.,Wasson, D.,Schmid, A.,Teng, I.T.,Zhou, T.,Kwong, P.D.,Currier, J.R.,Reiley, W.W.,Paquin-Proulx, D.,Polonis, V.R.,Collins, N.D.,Michael, N.L.,Joyce, M.G.,Krebs, S.J.
First-generation N-terminal domain supersite public antibodies retain activity against Omicron-derived lineages and protect mice against Omicron BA.5 challenge.
Mbio, 16:e0103625-e0103625, 2025

PubMed Abstract: Monoclonal antibodies to SARS-CoV-2 can offer prophylactic and therapeutic protection against severe disease, with particular utility for immunosuppressed and vulnerable populations. With the constant emergence of new variants, understanding the neutralizing potency of monoclonal antibodies to dynamic spike protein epitopes is crucial. We show that a set of VH1-24-derived N-terminal domain (NTD)-directed antibodies, isolated from a convalescent donor early in the pandemic, displayed remarkable neutralization resilience against many Omicron SARS-CoV-2 variants, including BA.2, BA.5, and BQ.1.1. Neutralization potency to these Omicron variants is associated with slower off-rates to the spike protein. Structural characterization of the most potent NTD antibody, WRAIR-2008, revealed a conserved mode of interaction shared with other antibodies of the same multi-donor class. WRAIR-2008 protected mice from weight loss following BA.5 challenge and reduced infectious viral titers in the lungs. Our study highlights the retention of neutralization activity and protection of first-generation VH1-24-derived NTD-directed antibodies to specific Omicron variants and provides valuable insights into the shifting landscape of SARS-CoV-2 variants that are vulnerable to select monoclonal antibodies.

PubMed: 40882161
DOI: 10.1128/mbio.01036-25

Experimental method

X-RAY DIFFRACTION (2.67 Å)