Oligomerization-driven avidity correlates with SARS-CoV-2 cellular binding and inhibition.
Proc Natl Acad Sci U S A
; 121(40): e2403260121, 2024 Oct.
Article
en En
| MEDLINE
| ID: mdl-39298475
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 11 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 11 binding strength. We show that ACE2 oligomerizes spike more strongly for more infectious variants, while exhibiting weaker 11 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Unión Proteica
/
Multimerización de Proteína
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Glicoproteína de la Espiga del Coronavirus
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Enzima Convertidora de Angiotensina 2
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SARS-CoV-2
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COVID-19
Límite:
Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2024
Tipo del documento:
Article
País de afiliación:
Reino Unido