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Localizing the Glycan Binding Sites of SARS-CoV-2 Receptor-Binding Domain
Linh Nguyen1,2, Elena N Kitova1, Martin A Rossotti3
1Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
Analytical Chemistry
|June 15, 2026
Summary
Researchers mapped the SARS-CoV-2 receptor-binding domain's (RBD) glycan-binding sites using antibody masking-native mass spectrometry (AM-nMS). This reveals multiple interaction surfaces crucial for understanding viral host interactions and developing therapeutics.
Area of Science:
- Structural Biology
- Virology
- Glycobiology
Background:
- Host-pathogen interactions are critical for viral pathogenesis.
- Understanding glycan binding by viral proteins aids therapeutic development.
- Specific glycan-binding residues on the SARS-CoV-2 receptor-binding domain (RBD) were previously undefined.
Purpose of the Study:
- To map the glycan-binding sites on the SARS-CoV-2 RBD at a residue level.
- To introduce and validate antibody masking-native mass spectrometry (AM-nMS) as a method for mapping glycan-binding sites.
Main Methods:
- Antibody masking-native mass spectrometry (AM-nMS) was employed.
- This technique combines nanobody targeting, center-of-mass monitoring, and catch-and-release strategies.
- Methods were validated using library screening, competitive binding, mass photometry, and molecular dynamics simulations.
Main Results:
- AM-nMS identified distinct, overlapping glycan-binding surfaces on the SARS-CoV-2 RBD.
- Heparan sulfate (HS) oligosaccharides bind to a groove overlapping the receptor-binding motif (RBM).
- Sialylated glycans and globoside glycans bind to additional sites, also partially overlapping the HS-binding region.
Conclusions:
- The SARS-CoV-2 RBD possesses multiple binding sites for diverse host glycans near the RBM.
- AM-nMS is a powerful and broadly applicable strategy for mapping protein-glycan interactions.
- This residue-level map provides insights into viral host interactions and potential therapeutic targets.
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