Neutralization of SARS-CoV-2 by destruction of the prefusion Spike

Jiandong HuoYuguang ZhaoJingshan RenDaming ZhouHelen M E DuyvesteynHelen M GinnLoic CarriqueTomas MalinauskasReinis R RuzaPranav NM ShahTiong Kit TanPramila RijalNaomi CoombesKevin BewleyJulika RadeckeNeil G PatersonPiyasa SupasaJuthathip MongkolsapayaGavin R ScreatonMiles CarrollAlain TownsendElizabeth E FryRaymond J OwensDavid I Stuart

There are as yet no licenced 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 (ACE2), initiating conformational changes that drive membrane fusion. We find that monoclonal antibody CR3022 binds the RBD tightly, neutralising SARS-CoV-2 and report the crystal structure at 2.4 angstrom of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilising, CR3022 epitope is inaccessible in the prefusion Spike, suggesting that CR3022 binding would facilitate conversion to the fusion-incompetent post-fusion state. 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 may be useful therapeutically, possibly in synergy with an antibody blocking receptor attachment.


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