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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(2024)

Univ Oxford

Cited 1|Views6
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 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 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.
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Key words
label- free single- molecule tracking,mass photometry,SARS-CoV-2,receptor oligomerization,avidity- based neutralization potency
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