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 Donat; Kerry Godwin; Karen R Buttigieg; Julia A Tree; Julika Radecke; Neil G Paterson; Piyada Supasa; Juthathip Mongkolsapaya; Gavin R Screaton; Miles W 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

doi:10.1038/s41594-020-0480-y

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

Nat Struct Mol Biol. 2020 Oct;27(10):950-958. doi: 10.1038/s41594-020-0480-y. Epub 2020 Jul 31.

Authors

Daming Zhou^#¹, Helen M E Duyvesteyn^#¹, Cheng-Pin Chen^#², Chung-Guei Huang^{3

4}, Ting-Hua Chen⁵, Shin-Ru Shih^{3

4}, Yi-Chun Lin⁶, Chien-Yu Cheng², Shu-Hsing Cheng⁶, Yhu-Chering Huang⁷, Tzou-Yien Lin⁷, Che Ma⁵, Jiandong Huo^{1

8

9}, Loic Carrique¹, Tomas Malinauskas¹, Reinis R Ruza¹, Pranav N M Shah¹, Tiong Kit Tan¹⁰, Pramila Rijal^{10

11}, Robert F Donat¹⁰, Kerry Godwin¹², Karen R Buttigieg¹², Julia A Tree¹², Julika Radecke¹³, Neil G Paterson¹³, Piyada Supasa¹⁴, Juthathip Mongkolsapaya^{14

15}, Gavin R Screaton¹⁴, Miles W Carroll^{12

14}, Javier Gilbert-Jaramillo¹⁶, Michael L Knight¹⁶, William James¹⁶, Raymond J Owens^{1

8

9}, James H Naismith^{1

8

9}, Alain R Townsend^{10

11}, Elizabeth E Fry¹, Yuguang Zhao^#¹, Jingshan Ren¹, David I Stuart^{17

18

19}, Kuan-Ying A Huang^{20

21}

Affiliations

¹ Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, UK.
² Department of Infectious Diseases, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, and National Yang-Ming University, Taipei, Taiwan.
³ Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
⁴ Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
⁵ Genomics Research Center, Academia Sinica, Taipei, Taiwan.
⁶ Department of Infectious Diseases, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, and Taipei Medical University, Taipei, Taiwan.
⁷ Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
⁸ The Rosalind Franklin Institute, Harwell Campus, Didcot, UK.
⁹ Protein Production UK, Research Complex at Harwell, Harwell Science & Innovation Campus, Didcot, UK.
¹⁰ MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
¹¹ Centre for Translational Immunology, Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK.
¹² National Infection Service, Public Health England, Porton Down, Salisbury, UK.
¹³ Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, UK.
¹⁴ Nuffield Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
¹⁵ Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
¹⁶ William Dunn School of Pathology, University of Oxford, Oxford, UK.
¹⁷ Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, UK. [email protected].
¹⁸ Centre for Translational Immunology, Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK. [email protected].
¹⁹ Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, UK. [email protected].
²⁰ Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, Taiwan. [email protected].
²¹ Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan. [email protected].

^# Contributed equally.

PMID: 32737466
DOI: 10.1038/s41594-020-0480-y

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 (K_D 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Angiotensin-Converting Enzyme 2
Animals
Antibodies, Neutralizing / immunology
Antibodies, Viral / chemistry*
Antibodies, Viral / immunology
Antibodies, Viral / metabolism
Betacoronavirus / chemistry*
Betacoronavirus / immunology
Betacoronavirus / metabolism
Binding Sites
COVID-19
Chlorocebus aethiops
Coronavirus Infections / immunology*
Cross Reactions
Cryoelectron Microscopy
Crystallography, X-Ray
Epitopes
Humans
Immunoglobulin Fab Fragments / chemistry
Immunoglobulin Fab Fragments / metabolism
Male
Pandemics
Peptidyl-Dipeptidase A / metabolism
Pneumonia, Viral / immunology*
Protein Conformation
Protein Domains
SARS-CoV-2
Spike Glycoprotein, Coronavirus / chemistry*
Spike Glycoprotein, Coronavirus / immunology
Spike Glycoprotein, Coronavirus / metabolism
Vero Cells

Substances

Antibodies, Neutralizing
Antibodies, Viral
Epitopes
Immunoglobulin Fab Fragments
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2
Peptidyl-Dipeptidase A
ACE2 protein, human
Angiotensin-Converting Enzyme 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding