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Author Notes:

Marie Pancera, Email: mpancera@fredhutch.org

N.K.H., A.T.M., L.S., and M.P. conceived the project. N.K.H., E.S., M.S., A.T.M., L.S., and M.P designed the experiments. J.F. cloned the plasmids. N.K.H. and A.B.S. expressed and purified the proteins. N.K.H. crystallized proteins, collected and processed the diffraction data, and solved the crystal structure. N.K.H. performed kinetic experiments. V.V.E. and Y.-H.W. performed neutralization assays. E.S. performed shedding experiments. N.K.H., A.T.M., L.S., and M.P. analyzed and discussed data. N.K.H. and M.P. wrote the original manuscript draft. N.K.H., A.T.M., L.S., and M.P. reviewed and edited the manuscript.

The authors declare no competing interests. A provisional patent application (U.S. Provisional Application number 63/016268) has been filed on the SARS-CoV-2-specific monoclonal antibodies isolated herein.

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Research Funding:

This work was supported by generous donations to Fred Hutch COVID-19 Research Fund. We thank Dr. McLellan for providing the SARS-CoV-2 RBD plasmid. We thank the J. B. Pendleton Charitable Trust for its generous support of Formulatrix robotic instruments. Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center (SBC), ID-19, at the Advanced Photon Source. SBC-CAT is operated by UChicago Argonne, LLC, for the U.S. Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. The SARS-CoV-2 neutralization assay efforts were in part supported by the Emory EVPHA Synergy Fund award, Center for Childhood Infections and Vaccines, Children’s Healthcare of Atlanta, COVID-Catalyst-I3 Funds from the Woodruff Health Sciences Center and Emory School of Medicine.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics

Structural basis for potent neutralization of SARS-CoV-2 and role of antibody affinity maturation

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Journal Title:

NATURE COMMUNICATIONS

Volume:

Volume 11, Number 1

Publisher:

, Pages 5413-5413

Type of Work:

Article | Final Publisher PDF

Abstract:

SARS-CoV-2 is a betacoronavirus virus responsible for the COVID-19 pandemic. Here, we determine the X-ray crystal structure of a potent neutralizing monoclonal antibody, CV30, isolated from a patient infected with SARS-CoV-2, in complex with the receptor binding domain. The structure reveals that CV30 binds to an epitope that overlaps with the human ACE2 receptor binding motif providing a structural basis for its neutralization. CV30 also induces shedding of the S1 subunit, indicating an additional mechanism of neutralization. A germline reversion of CV30 results in a substantial reduction in both binding affinity and neutralization potential indicating the minimal somatic mutation is needed for potently neutralizing antibodies against SARS-CoV-2.

Copyright information:

© The Author(s) 2020

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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