7WC0

Crystal structure of Fab region of TAU-2212 neutralizing SARS-CoV-2

Summary for 7WC0

• Entry DOI: 10.2210/pdb7wc0/pdb
• Descriptor: TAU-2212 Heavy chain, TAU-2212 Light chain (3 entities in total)
• Functional Keywords: immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 4
• Total formula weight: 103960.40

Authors

Xiang, Y.,Li, R.,Ma, B. (deposition date: 2021-12-17, release date: 2022-08-10, Last modification date: 2023-11-29)

Primary citation

Li, R.,Mor, M.,Ma, B.,Clark, A.E.,Alter, J.,Werbner, M.,Lee, J.C.,Leibel, S.L.,Carlin, A.F.,Dessau, M.,Gal-Tanamy, M.,Croker, B.A.,Xiang, Y.,Freund, N.T.
Conformational flexibility in neutralization of SARS-CoV-2 by naturally elicited anti-SARS-CoV-2 antibodies.
Commun Biol, 5:789-789, 2022

PubMed Abstract: As new variants of SARS-CoV-2 continue to emerge, it is important to assess the cross-neutralizing capabilities of antibodies naturally elicited during wild type SARS-CoV-2 infection. In the present study, we evaluate the activity of nine anti-SARS-CoV-2 monoclonal antibodies (mAbs), previously isolated from convalescent donors infected with the Wuhan-Hu-1 strain, against the SARS-CoV-2 variants of concern (VOC) Alpha, Beta, Gamma, Delta and Omicron. By testing an array of mutated spike receptor binding domain (RBD) proteins, cell-expressed spike proteins from VOCs, and neutralization of SARS-CoV-2 VOCs as pseudoviruses, or as the authentic viruses in culture, we show that mAbs directed against the ACE2 binding site (ACE2bs) are more sensitive to viral evolution compared to anti-RBD non-ACE2bs mAbs, two of which retain their potency against all VOCs tested. At the second part of our study, we reveal the neutralization mechanisms at high molecular resolution of two anti-SARS-CoV-2 neutralizing mAbs by structural characterization. We solve the structures of the Delta-neutralizing ACE2bs mAb TAU-2303 with the SARS-CoV-2 spike trimer and RBD at 4.5 Å and 2.42 Å resolutions, respectively, revealing a similar mode of binding to that between the RBD and ACE2. Furthermore, we provide five additional structures (at resolutions of 4.7 Å, 7.3 Å, 6.4 Å, 3.3 Å, and 6.1 Å) of a second antibody, TAU-2212, complexed with the SARS-CoV-2 spike trimer. TAU-2212 binds an exclusively quaternary epitope, and exhibits a unique, flexible mode of neutralization that involves transitioning between five different conformations, with both arms of the antibody recruited for cross linking intra- and inter-spike RBD subunits. Our study provides additional mechanistic understanding about how antibodies neutralize SARS-CoV-2 and its emerging variants and provides insights on the likelihood of reinfections.

PubMed: 35931732
DOI: 10.1038/s42003-022-03739-5

Experimental method

X-RAY DIFFRACTION (2.705 Å)