Conformational Flexibility in Neutralization of SARS-CoV-2 by Naturally Elicited Anti-SARS-CoV-2 Antibodies
Conformational Flexibility in Neutralization of SARS-CoV-2 by Naturally Elicited Anti-SARS-CoV-2 Antibodies
ABSTRACT As new variants of SARS-CoV-2 continue to emerge, it is important to assess the neutralizing capabilities of naturally elicited antibodies against SARS-CoV-2. In the present study, we evaluated 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 pseudoviuses, or as the authentic viruses in culture, we show that mAbs directed against the ACE2 binding site (ACE2bs) are far more sensitive to viral evolution compared to anti-RBD non-ACE2bs mAbs, two of which kept 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 solved the structures of the Delta-neutralizing ACE2bs mAb TAU-2303 with the SARS-CoV-2 spike trimer and RBD at 4.5 ? and 2.42 ?, respectively, revealing a similar mode of binding to that between the RBD and the ACE2 receptor. Furthermore, we provide five additional structures (at resolutions of 5.54 ?, 7.76 ?, 6.47 ?, 3.45 ?, and 7.32 ?) of a second antibody, non-ACE2bs mAb 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 new mechanistic insights about how antibodies neutralize SARS-CoV-2 and its emerging variants and provides insight about the likelihood of reinfections.
Xiang Ye、Li Ruofan、Ma Bingting、Lee Jamie Casey、Leibel Sandra L.、Carlin Aaron F.、Mor Michael、Croker Ben A.、Dessau Moshe、Werbner Michal、Freund Natalia T.、Gal-Tanamy Meital、Alter Joel、Clark Alex E.
Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Center for Infectious Disease Research, School of Medicine, Tsinghua UniversityBeijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Center for Infectious Disease Research, School of Medicine, Tsinghua UniversityBeijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Center for Infectious Disease Research, School of Medicine, Tsinghua UniversityDepartment of Pediatrics, School of Medicine, UC San DiegoDepartment of Pediatrics, School of Medicine, UC San Diego||Sanford Burnham Prebys Medical Discovery Institute||Sanford Consortium for Regenerative MedicineDepartment of Medicine, University of California San DiegoDepartment for Microbiology and Clinical Immunology, Faculty of Medicine, Tel Aviv UniversityDepartment of Pediatrics, School of Medicine, UC San DiegoThe Laboratory of Structural Biology of Infectious Diseases, Azrieli Faculty of Medicine, Bar Ilan UniversityMolecular Virology Lab, Azrieli Faculty of Medicine, Bar Ilan UniversityDepartment for Microbiology and Clinical Immunology, Faculty of Medicine, Tel Aviv UniversityMolecular Virology Lab, Azrieli Faculty of Medicine, Bar Ilan UniversityThe Laboratory of Structural Biology of Infectious Diseases, Azrieli Faculty of Medicine, Bar Ilan UniversityDepartment of Medicine, University of California San Diego
医药卫生理论医学研究方法基础医学
Xiang Ye,Li Ruofan,Ma Bingting,Lee Jamie Casey,Leibel Sandra L.,Carlin Aaron F.,Mor Michael,Croker Ben A.,Dessau Moshe,Werbner Michal,Freund Natalia T.,Gal-Tanamy Meital,Alter Joel,Clark Alex E..Conformational Flexibility in Neutralization of SARS-CoV-2 by Naturally Elicited Anti-SARS-CoV-2 Antibodies[EB/OL].(2025-03-28)[2025-05-11].https://www.biorxiv.org/content/10.1101/2022.04.03.486854.点此复制
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