7K9I

SARS-CoV-2 Spike RBD in complex with neutralizing Fab 2B04 (local refinement)

Summary for 7K9I

• Entry DOI: 10.2210/pdb7k9i/pdb
• Related: 7K9H 7K9J 7K9K
• EMDB information: 22748 22749 22750 22751 22752 22753
• Descriptor: Spike protein S1, 2B04 heavy chain, 2B04 light chain, ... (4 entities in total)
• Functional Keywords: complex, neutralizing antibody, ace2-competitive, receptor-binding domain, structural genomics, center for structural genomics of infectious diseases, csgid, viral protein-immune system complex, viral protein/immune system
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV); More
• Total number of polymer chains: 3
• Total formula weight: 46788.25

Authors

Errico, J.M.,Fremont, D.H.,Center for Structural Genomics of Infectious Diseases (CSGID) (deposition date: 2020-09-29, release date: 2021-09-29, Last modification date: 2024-11-13)

Primary citation

Errico, J.M.,Zhao, H.,Chen, R.E.,Liu, Z.,Case, J.B.,Ma, M.,Schmitz, A.J.,Rau, M.J.,Fitzpatrick, J.A.J.,Shi, P.Y.,Diamond, M.S.,Whelan, S.P.J.,Ellebedy, A.H.,Fremont, D.H.
Structural mechanism of SARS-CoV-2 neutralization by two murine antibodies targeting the RBD.
Cell Rep, 37:109881-109881, 2021

PubMed Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has necessitated the rapid development of antibody-based therapies and vaccines as countermeasures. Here, we use cryoelectron microscopy (cryo-EM) to characterize two protective anti-SARS-CoV-2 murine monoclonal antibodies (mAbs) in complex with the spike protein, revealing similarities between epitopes targeted by human and murine B cells. The more neutralizing mAb, 2B04, binds the receptor-binding motif (RBM) of the receptor-binding domain (RBD) and competes with angiotensin-converting enzyme 2 (ACE2). By contrast, 2H04 binds adjacent to the RBM and does not compete for ACE2 binding. Naturally occurring sequence variants of SARS-CoV-2 and corresponding neutralization escape variants selected in vitro map to our structurally defined epitopes, suggesting that SARS-CoV-2 might evade therapeutic antibodies with a limited set of mutations, underscoring the importance of combination mAb therapeutics. Finally, we show that 2B04 neutralizes SARS-CoV-2 infection by preventing ACE2 engagement, whereas 2H04 reduces host cell attachment without directly disrupting ACE2-RBM interactions, providing distinct inhibitory mechanisms used by RBD-specific mAbs.

PubMed: 34655519
DOI: 10.1016/j.celrep.2021.109881

Experimental method

ELECTRON MICROSCOPY (3.3 Å)