Mass photometry reveals SARS-CoV-2 spike stabilisation to impede ACE2 binding through altered conformational dynamics

Journal article

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: Burnap, SA; Struwe, WB

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Royal Society of Chemistry
• Journal: Chemical Communications
• Volume: 58
• Issue: 93
• Pages: 12939-12942
• Publication date: 2022-11-22
• DOI: 10.1039/d2cc04711j
• EISSN: 1364-548X
• ISSN: 1359-7345
• Language: English
• Keywords: Biophysics; Biology; Coronavirus disease 2019 (COVID-19); Dynamics (music); Spike (software development); Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); Outbreak; Computer science; Virology; Infectious disease (medical specialty); Spike Protein; Astrophysics; 2019-20 coronavirus outbreak; Chemistry; Photometry (optics); Medicine; Physics