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.
Cell Host Microbe
445 - 454.e6
CR3022, SARS-CoV-2, X-ray crystallography, antibody, cryo-electron microscopy, epitope, neutralization, receptor binding domain, spike, therapeutic, Allosteric Site, Amino Acid Sequence, Angiotensin-Converting Enzyme 2, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Antigen-Antibody Complex, Betacoronavirus, COVID-19, COVID-19 Vaccines, Coronavirus Infections, Cryoelectron Microscopy, Crystallography, X-Ray, Host Microbial Interactions, Humans, Models, Molecular, Neutralization Tests, Pandemics, Peptidyl-Dipeptidase A, Pneumonia, Viral, Receptors, Virus, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Viral Vaccines, Virus Internalization