Journal
CELL HOST & MICROBE
Volume 28, Issue 3, Pages 445-+Publisher
CELL PRESS
DOI: 10.1016/j.chom.2020.06.010
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Funding
- CAMS-Oxford Institute
- Wellcome Trust [101122/Z/13/Z, 095541/A/11/Z, 090532/Z/09/Z]
- Cancer Research UK [C375/A17721, C20724/A14414, C20724/A26752]
- UK Medical Research Council [MR/N00065X/1]
- EPA Cephalosporin Fund
- Rosalind Franklin Institute EPSRC grant [EP/S025243/1]
- Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS) [2018-I2M-2-002]
- National Institutes for Health Research Biomedical Research Centre Funding Scheme
- EPSRC [EP/S025243/1] Funding Source: UKRI
- MRC [MR/N00065X/1] Funding Source: UKRI
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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 angstrom 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.
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