9YPR

Fab-14/SARS-CoV-2 D614G spike complex, Mode IV, subgroup I conformation

Summary for 9YPR

• Entry DOI: 10.2210/pdb9ypr/pdb
• Related: 9YNR 9YNX 9YOK 9YPB
• EMDB information: 73228 73231 73244 73245 73247 73260 73263 73265 73267 73270 73271 73273 73290 73291 73292 73306
• Descriptor: Spike glycoprotein, Fab-14 heavy chain, Fab-14 light chain, ... (5 entities in total)
• Functional Keywords: sars-cov-2, neutralizing antibody, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2); More
• Total number of polymer chains: 7
• Total formula weight: 530032.08

Authors

Wang, Y.,Hu, Y.,Leiman, P.,Xie, X. (deposition date: 2025-10-14, release date: 2026-03-18, Last modification date: 2026-04-08)

Primary citation

Wang, Y.,Hu, Y.,Ku, Z.,Yeung, J.,Zou, J.,Woodson, M.,Prokhorov, N.S.,Knyazhanskaya, E.S.,Zhao, H.,Sherman, M.B.,An, Z.,Carroll, S.F.,Shi, P.Y.,Leiman, P.G.,Xie, X.
Neutralization of SARS-CoV-2 by IgM-14 via engagement of two distinct spike epitopes.
Plos Pathog., 22:e1014071-e1014071, 2026

PubMed Abstract: Engineered immunoglobulin M (IgM) antibodies typically exhibit superior neutralization potency and avidity compared to their parental IgG counterparts, primarily due to multivalent binding to repeated epitopes on a targeting antigen. In this study, we characterize the neutralization breadth and mechanism of action of IgM-14, a previously reported intranasally deliverable antibody targeting SARS-CoV-2. IgM-14 demonstrates remarkably potent antiviral activity against all pre-Omicron variants but significantly reduced efficacy against Omicron BA.1, and complete loss of activity against the later subvariant JN.1. Resistance selection identified two key mutations in the receptor-binding domain (RBD), G476D and F486P, which disrupt IgM-14 binding and confer strong resistance. Cryo-electron microscopy analysis uncovered two distinct Fab-RBD interfaces: a primary interface overlapping the angiotensin-converting enzyme 2 (ACE2)-binding region, and a unique secondary interface formed only when the RBD adopts the ACE2-inaccessible "down" conformation, involving a neighboring spike protomer. Site-directed mutagenesis and structural modeling revealed a critical role of this secondary site in IgM-14-mediated neutralization. Unlike IgG-14, structural modeling suggested that IgM-14 can simultaneously engage both interfaces in diverse modes, indicating a noncanonical avidity mechanism. Collectively, these findings highlight the structural and functional uniqueness of IgM-14 and offer valuable insights into the rational design of next-generation spike-targeted antibody therapeutics with enhanced breadth and potency.

PubMed: 41880376
DOI: 10.1371/journal.ppat.1014071

Experimental method

ELECTRON MICROSCOPY (3.46 Å)