@article{Asor_R-2024_189435,
title = {Oligomerization-driven avidity correlates with SARS-CoV-2 cellular binding and inhibition},
author = {Asor, R. and Olerinyova, A. and Burnap, S. and Kushwah, M. and Soltermann, F. and Rudden, L. and Hensen, M. and Vasiljevic, S. and Brun, J. and Hill, M. and Chang, L. and Dejnirattisai, W. and Supasa, P. and Mongkolsapaya, J. and Zhou, D. and Stuart, D. and Screaton, G. and Degiacomi, M. and Zitzmann, N. and Benesch, J. and Struwe, W. and Kukura, P.},
month = {sep},
year = {2024},
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.},
volume = {121},
issue = {40},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
publisher = {National Academy of Sciences},
url = {https://doi.org/10.5287/ora-1zppvdavr},
}
