Oligomerization-driven avidity correlates with SARS-CoV-2 cellular binding and inhibition
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.
Authors
- Weston B. Struwe (ORCID: https://orcid.org/0000-0003-0594-226X)
- Snežana Vasiljević (ORCID: https://orcid.org/0000-0002-8886-6225)
- Mario Hensen (ORCID: https://orcid.org/0000-0002-2200-5975)
- Philipp Kukura (ORCID: https://orcid.org/0000-0003-0136-7704)
- Nicole Zitzmann (ORCID: https://orcid.org/0000-0003-1969-4949)
- Daming Zhou (ORCID: https://orcid.org/0000-0002-7188-5243)
- Lucas S. P. Rudden (ORCID: https://orcid.org/0000-0002-4753-8890)
- Sean A. Burnap (ORCID: https://orcid.org/0000-0002-3408-8608)
- Manish S. Kushwah (ORCID: https://orcid.org/0000-0001-5088-0403)
- David I. Stuart (ORCID: https://orcid.org/0000-0002-3426-4210)
- Michelle L. Hill (ORCID: https://orcid.org/0000-0002-9289-5811)
- Juthathip Mongkolsapaya (ORCID: https://orcid.org/0000-0003-3416-9480)
- Fabian Soltermann (ORCID: https://orcid.org/0000-0002-8616-9346)
- Roi Asor (ORCID: https://orcid.org/0000-0002-5206-4378)
- Matteo T. Degiacomi (ORCID: https://orcid.org/0000-0003-4672-471X)
- Wanwisa Dejnirattisai
- Juliane Brun (ORCID: https://orcid.org/0000-0002-0964-3681)
- Anna Olerinyova (ORCID: https://orcid.org/0000-0002-0358-4262)
- Justin L. P. Benesch (ORCID: https://orcid.org/0000-0002-1507-3742)
- Gavin Robert Screaton (ORCID: https://orcid.org/0000-0002-3549-4309)
- Chang Liu (ORCID: https://orcid.org/0009-0008-8169-4572)
- Piyada Supasa
Institutions
- National Health Service (GB)
- Siriraj Hospital (TH)
- Centre for Human Genetics (GB)
- Durham University (GB)
- Mahidol University (TH)
- Oxford Health NHS Foundation Trust (GB)
- Diamond Light Source (GB)
- University of Oxford (GB)
- Science Oxford (GB)
- Oxford University Hospitals NHS Trust (GB)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2024-09-19
- DOI
- https://doi.org/10.1073/pnas.2403260121
- Citations
- 13
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 5.06
Funders
- Medical Research Council
- Engineering and Physical Sciences Research Council
- Biotechnology and Biological Sciences Research Council