Oligomerisation-driven avidity controls SARS-CoV-2 cellular binding and inhibition
Asor R., Olerinyova A., Burnap S., Kushwah M., Soltermann F., Rudden L., Hensen M., Vasiljevic S., Brun J., Hill M., Chang L., Dejnirattisa W., Supasa P., Mongkolsapaya J., Zhou D., Stuart D., Screaton GR., Degiacomi M., Zitzmann N., Benesch J., Struwe W., Kukura P.
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 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 find that ACE2 oligomerises spike more strongly for more infectious variants, while exhibiting weaker 1:1 affinity. Furthermore, we find that antibodies use induced-oligomerisation both as a primary inhibition mechanism and to enhance the effects of receptor-site blocking. Our results reveal that naive affinity measurements are poor predictors of potency, and introduce a novel antibody-based inhibition mechanism for oligomeric targets. More generally, they point towards a much broader role of induced oligomerisation in controlling biomolecular interactions.