Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient

Daming Zhou, Helen M.E. Duyvesteyn, Cheng Pin Chen, Chung Guei Huang, Ting Hua Chen, Shin Ru Shih, Yi Chun Lin, Chien Yu Cheng, Shu Hsing Cheng, Yhu Chering Huang, Tzou Yien Lin, Che Ma, Jiandong Huo, Loic Carrique, Tomas Malinauskas, Reinis R. Ruza, Pranav N.M. Shah, Tiong Kit Tan, Pramila Rijal, Robert F. DonatKerry Godwin, Karen R. Buttigieg, Julia A. Tree, Julika Radecke, Neil G. Paterson, Piyada Supasa, Juthathip Mongkolsapaya, Gavin R. Screaton, Miles Carroll, Javier Gilbert-Jaramillo, Michael L. Knight, William James, Raymond J. Owens, James H. Naismith, Alain R. Townsend, Elizabeth E. Fry, Yuguang Zhao, Jingshan Ren, David I. Stuart*, Kuan Ying A. Huang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

157 Citations (Scopus)

Abstract

The COVID-19 pandemic has had an unprecedented health and economic impact and there are currently no approved therapies. We have isolated an antibody, EY6A, from an individual convalescing from COVID-19 and have shown that it neutralizes SARS-CoV-2 and cross-reacts with SARS-CoV-1. EY6A Fab binds the receptor binding domain (RBD) of the viral spike glycoprotein tightly (KD of 2 nM), and a 2.6-Å-resolution crystal structure of an RBD–EY6A Fab complex identifies the highly conserved epitope, away from the ACE2 receptor binding site. Residues within this footprint are key to stabilizing the pre-fusion spike. Cryo-EM analyses of the pre-fusion spike incubated with EY6A Fab reveal a complex of the intact spike trimer with three Fabs bound and two further multimeric forms comprising the destabilized spike attached to Fab. EY6A binds what is probably a major neutralizing epitope, making it a candidate therapeutic for COVID-19.

Original languageEnglish
Pages (from-to)950-958
Number of pages9
JournalNature Structural and Molecular Biology
Volume27
Issue number10
DOIs
Publication statusPublished - 1 Oct 2020

Bibliographical note

Funding Information:
We acknowledge the BD FACSAria cell sorter service provided by the Core Instrument Center of Chang Gung University. The sorting of plasmablasts and production and characterization of human mAbs were supported by the Chang Gung Memorial Hospital (BMRPE22). This work was supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China (grant no. 2018-I2M-2-002) to D.I.S., G.R.S. and A.R.T., which supported P.R.; E.E.F., H.M.E.D. and J. Ren are supported by the Wellcome Trust (101122/Z/13/Z); Y.Z. by Cancer Research UK (C375/ A17721); and D.I.S. and E.E.F. by the UK Medical Research Council (MR/N00065X/1); J.H. is supported by a grant from the EPA Cephalosporin Fund; and PPUK is funded by the Rosalind Franklin Institute EPSRC grant no. EP/S025243/1 (J.H.N. and R.J.O.). The National Institute for Health Research Biomedical Research Centre Funding Scheme supports G.R.S. We are also grateful for a Fast Grant from Fast Grants (Mercatus Center) to support the isolation of human monoclonal antibodies to SARS-2. G.R.S. is also supported as a Wellcome Trust Senior Investigator (grant no. 095541/A/11/Z). T.K.T. is funded by an EPA Cephalosporin Early Career Teaching and Research Fellowship and the Townsend-Jeantet Charitable Trust (charity no. 1011770). T.M. is supported by Cancer Research UK grants C20724/A14414 and C20724/A26752 to C. Siebold. This is a contribution from the UK Instruct-ERIC Centre. The Wellcome Centre for Human Genetics is supported by the Wellcome Trust (grant no. 090532/Z/09/Z). Virus used for the neutralization assays was a gift from J. Druce at the Doherty Centre, Melbourne, Australia. We acknowledge the Diamond Light Source for time on Beamline I03 under proposal mx19946 and for electron microscope time at the UK National Electron Bio-Imaging Centre (eBIC), proposal BI26983, both COVID-19 Rapid Access. D.I.S. is a Jenner Investigator. We thank the teams, especially at the Diamond Light Source and Department of Structural Biology, Oxford University, that have enabled work to continue during the pandemic.

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