Cell Host & Microbe
Volume 28, Issue 3, 9 September 2020, Pages 445-454.e6
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Article
Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike

https://doi.org/10.1016/j.chom.2020.06.010Get rights and content
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Highlights

  • CR3022 binds the RBD of SARS-CoV-2 and shows strong neutralization

  • Neutralization is by destroying the prefusion spike conformation

  • CR3022 binds a highly conserved epitope that is inaccessible in prefusion spike protein

  • CR3022 could have therapeutic potential alone or in synergy with a receptor blocker

Summary

There are as yet no licensed therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric spike whose receptor binding domain (RBD) recognizes angiotensin-converting enzyme 2, initiating conformational changes that drive membrane fusion. We find that the monoclonal antibody CR3022 binds the RBD tightly, neutralizing SARS-CoV-2, and report the crystal structure at 2.4 Å of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilizing CR3022 epitope is inaccessible in the prefusion spike, suggesting that CR3022 binding facilitates conversion to the fusion-incompetent post-fusion state. Cryogenic electron microscopy (cryo-EM) analysis confirms that incubation of spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope could be useful therapeutically, possibly in synergy with an antibody that blocks receptor attachment.

Keywords

neutralization
antibody
SARS-CoV-2
spike
receptor binding domain
epitope
therapeutic
CR3022
cryo-electron microscopy
X-ray crystallography

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11

These authors contributed equally

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