Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

The SARS-CoV-2 virus is more transmissible than previous coronaviruses and causes a more serious illness than influenza. The SARS-CoV-2 receptor binding domain (RBD) of the spike protein binds to the human angiotensin-converting enzyme 2 (ACE2) receptor as a prelude to viral entry into the cell. Using a naive llama single-domain antibody library and PCR-based maturation, we have produced two closely related nanobodies, H11-D4 and H11-H4, that bind RBD (KD of 39 and 12 nM, respectively) and block its interaction with ACE2. Single-particle cryo-EM revealed that both nanobodies bind to all three RBDs in the spike trimer. Crystal structures of each nanobody-RBD complex revealed how both nanobodies recognize the same epitope, which partly overlaps with the ACE2 binding surface, explaining the blocking of the RBD-ACE2 interaction. Nanobody-Fc fusions showed neutralizing activity against SARS-CoV-2 (4-6 nM for H11-H4, 18 nM for H11-D4) and additive neutralization with the SARS-CoV-1/2 antibody CR3022.

Original publication

DOI

10.1038/s41594-020-0469-6

Type

Journal article

Journal

Nat Struct Mol Biol

Publication Date

09/2020

Volume

27

Pages

846 - 854

Keywords

Amino Acid Sequence, Angiotensin-Converting Enzyme 2, Antibodies, Neutralizing, Antibodies, Viral, Antibody Affinity, Antigen-Antibody Reactions, Betacoronavirus, Binding, Competitive, COVID-19, Coronavirus Infections, Cryoelectron Microscopy, Crystallography, X-Ray, Epitopes, Humans, Immunoglobulin Fc Fragments, Models, Molecular, Pandemics, Peptide Library, Peptidyl-Dipeptidase A, Pneumonia, Viral, Protein Binding, Protein Conformation, Receptors, Virus, Recombinant Fusion Proteins, SARS-CoV-2, Sequence Homology, Amino Acid, Single-Domain Antibodies, Spike Glycoprotein, Coronavirus