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 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

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 journal › Article › peer-review

221 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 (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.

Original language	English
Pages (from-to)	950-958
Number of pages	9
Journal	Nature Structural and Molecular Biology
Volume	27
Issue number	10
Early online date	31 Jul 2020
DOIs	https://doi.org/10.1038/s41594-020-0480-y
Publication status	Published - 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.

Open Access: Free to read, but no Open Access licence.

Publisher copyright: Copyright © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

Citation: Zhou, D., Duyvesteyn, H.M.E., Chen, CP. et al. Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient. Nat Struct Mol Biol 27, 950–958 (2020). https://doi.org/10.1038/s41594-020-0480-y

DOI: https://doi.org/10.1038/s41594-020-0480-y

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Zhou, D., Duyvesteyn, H. M. E., Chen, C. P., Huang, C. G., Chen, T. H., Shih, S. R., Lin, Y. C., Cheng, C. Y., Cheng, S. H., Huang, Y. C., Lin, T. Y., Ma, C., Huo, J., Carrique, L., Malinauskas, T., Ruza, R. R., Shah, P. N. M., Tan, T. K., Rijal, P., ... Huang, K. Y. A. (2020). Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient. Nature Structural and Molecular Biology, 27(10), 950-958. https://doi.org/10.1038/s41594-020-0480-y

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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-{\AA}-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.",

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

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. Open Access: Free to read, but no Open Access licence. Publisher copyright: Copyright {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. Citation: Zhou, D., Duyvesteyn, H.M.E., Chen, CP. et al. Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient. Nat Struct Mol Biol 27, 950–958 (2020). https://doi.org/10.1038/s41594-020-0480-y DOI: https://doi.org/10.1038/s41594-020-0480-y",

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doi = "10.1038/s41594-020-0480-y",

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Zhou, D, Duyvesteyn, HME, Chen, CP, Huang, CG, Chen, TH, Shih, SR, Lin, YC, Cheng, CY, Cheng, SH, Huang, YC, Lin, TY, Ma, C, Huo, J, Carrique, L, Malinauskas, T, Ruza, RR, Shah, PNM, Tan, TK, Rijal, P, Donat, RF, Godwin, K , Buttigieg, KR , Tree, JA, Radecke, J, Paterson, NG, Supasa, P, Mongkolsapaya, J, Screaton, GR, Carroll, M, Gilbert-Jaramillo, J, Knight, ML, James, W, Owens, RJ, Naismith, JH, Townsend, AR, Fry, EE, Zhao, Y, Ren, J, Stuart, DI & Huang, KYA 2020, 'Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient', Nature Structural and Molecular Biology, vol. 27, no. 10, pp. 950-958. https://doi.org/10.1038/s41594-020-0480-y

TY - JOUR

T1 - Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient

AU - Zhou, Daming

AU - Duyvesteyn, Helen M.E.

AU - Chen, Cheng Pin

AU - Huang, Chung Guei

AU - Chen, Ting Hua

AU - Shih, Shin Ru

AU - Lin, Yi Chun

AU - Cheng, Chien Yu

AU - Cheng, Shu Hsing

AU - Huang, Yhu Chering

AU - Lin, Tzou Yien

AU - Ma, Che

AU - Huo, Jiandong

AU - Carrique, Loic

AU - Malinauskas, Tomas

AU - Ruza, Reinis R.

AU - Shah, Pranav N.M.

AU - Tan, Tiong Kit

AU - Rijal, Pramila

AU - Donat, Robert F.

AU - Godwin, Kerry

AU - Buttigieg, Karen R.

AU - Tree, Julia A.

AU - Radecke, Julika

AU - Paterson, Neil G.

AU - Supasa, Piyada

AU - Mongkolsapaya, Juthathip

AU - Screaton, Gavin R.

AU - Carroll, Miles

AU - Gilbert-Jaramillo, Javier

AU - Knight, Michael L.

AU - James, William

AU - Owens, Raymond J.

AU - Naismith, James H.

AU - Townsend, Alain R.

AU - Fry, Elizabeth E.

AU - Zhao, Yuguang

AU - Ren, Jingshan

AU - Stuart, David I.

AU - Huang, Kuan Ying A.

N1 - 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. Open Access: Free to read, but no Open Access licence. Publisher copyright: Copyright © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. Citation: Zhou, D., Duyvesteyn, H.M.E., Chen, CP. et al. Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient. Nat Struct Mol Biol 27, 950–958 (2020). https://doi.org/10.1038/s41594-020-0480-y DOI: https://doi.org/10.1038/s41594-020-0480-y

PY - 2020/10/1

Y1 - 2020/10/1

N2 - 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.

AB - 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.

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DO - 10.1038/s41594-020-0480-y

M3 - Article

C2 - 32737466

AN - SCOPUS:85088842557

SN - 1545-9993

VL - 27

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JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

IS - 10

ER -

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

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