Oligomerization-driven avidity correlates with SARS-CoV-2 cellular binding and inhibition
Issued Date
2024-10-01
Resource Type
eISSN
10916490
Scopus ID
2-s2.0-85204512084
Pubmed ID
39298475
Journal Title
Proceedings of the National Academy of Sciences of the United States of America
Volume
121
Issue
40
Rights Holder(s)
SCOPUS
Bibliographic Citation
Proceedings of the National Academy of Sciences of the United States of America Vol.121 No.40 (2024)
Suggested Citation
Asor R., Olerinyova A., Burnap S.A., Kushwah M.S., Soltermann F., Rudden L.S.P., Hensen M., Vasiljevic S., Brun J., Hill M., Chang L., Dejnirattisai W., Supasa P., Mongkolsapaya J., Zhou D., Stuart D.I., Screaton G.R., Degiacomi M.T., Zitzmann N., Benesch J.L.P., Struwe W.B., Kukura P. Oligomerization-driven avidity correlates with SARS-CoV-2 cellular binding and inhibition. Proceedings of the National Academy of Sciences of the United States of America Vol.121 No.40 (2024). doi:10.1073/pnas.2403260121 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/101404
Title
Oligomerization-driven avidity correlates with SARS-CoV-2 cellular binding and inhibition
Corresponding Author(s)
Other Contributor(s)
Abstract
Cellular processes are controlled by the thermodynamics of the underlying biomolecular interactions. Frequently, structural investigations use one monomeric binding partner, while ensemble measurements of binding affinities generally yield one affinity representative of a 1:1 interaction, despite the majority of the proteome consisting of oligomeric proteins. For example, viral entry and inhibition in SARS-CoV-2 involve a trimeric spike surface protein, a dimeric angiotensin-converting enzyme 2 (ACE2) cell-surface receptor and dimeric antibodies. Here, we reveal that cooperativity correlates with infectivity and inhibition as opposed to 1:1 binding strength. We show that ACE2 oligomerizes spike more strongly for more infectious variants, while exhibiting weaker 1:1 affinity. Furthermore, we find that antibodies use induced oligomerization both as a primary inhibition mechanism and to enhance the effects of receptor-site blocking. Our results suggest that naive affinity measurements are poor predictors of potency, and introduce an antibody-based inhibition mechanism for oligomeric targets. More generally, they point toward a much broader role of induced oligomerization in controlling biomolecular interactions.
