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Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike.
Cell Host Microbe. 2020 09 09; 28(3):445-454.e6.CH

Abstract

There are as yet no licensed therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric spike whose receptor binding domain (RBD) recognizes angiotensin-converting enzyme 2, initiating conformational changes that drive membrane fusion. We find that the monoclonal antibody CR3022 binds the RBD tightly, neutralizing SARS-CoV-2, and report the crystal structure at 2.4 Å of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilizing CR3022 epitope is inaccessible in the prefusion spike, suggesting that CR3022 binding facilitates conversion to the fusion-incompetent post-fusion state. Cryogenic electron microscopy (cryo-EM) analysis confirms that incubation of spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope could be useful therapeutically, possibly in synergy with an antibody that blocks receptor attachment.

Authors+Show Affiliations

Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK; The Rosalind Franklin Institute, Harwell Campus, OX11 0FA, UK; Protein Production UK, Research Complex at Harwell, Harwell Science & Innovation Campus, Didcot, OX11 0FA, UK.Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK.Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK. Electronic address: ren@strubi.ox.ac.uk.Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK.Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK.Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, OX11 0DE, UK.Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK.Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK.Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK.Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK.MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK; Centre for Translational Immunology, Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford OX3 7FZ, UK.National Infection Service, Public Health England, Porton Down, Salisbury, SP4 0JG, UK.National Infection Service, Public Health England, Porton Down, Salisbury, SP4 0JG, UK.National Infection Service, Public Health England, Porton Down, Salisbury, SP4 0JG, UK.Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, OX11 0DE, UK.Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, OX11 0DE, UK.Nuffield Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.Nuffield Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK; Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 73170, Thailand.Nuffield Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.National Infection Service, Public Health England, Porton Down, Salisbury, SP4 0JG, UK; Nuffield Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK; Centre for Translational Immunology, Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford OX3 7FZ, UK.Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK.Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK; The Rosalind Franklin Institute, Harwell Campus, OX11 0FA, UK; Protein Production UK, Research Complex at Harwell, Harwell Science & Innovation Campus, Didcot, OX11 0FA, UK.Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, OX3 7BN, UK; Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, OX11 0DE, UK; Instruct-ERIC, Oxford House, Parkway Court, John Smith Drive, Oxford, OX4 2JY, UK. Electronic address: dave@strubi.ox.ac.uk.

Pub Type(s)

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

Language

eng

PubMed ID

32585135

Citation

Huo, Jiandong, et al. "Neutralization of SARS-CoV-2 By Destruction of the Prefusion Spike." Cell Host & Microbe, vol. 28, no. 3, 2020, pp. 445-454.e6.
Huo J, Zhao Y, Ren J, et al. Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike. Cell Host Microbe. 2020;28(3):445-454.e6.
Huo, J., Zhao, Y., Ren, J., Zhou, D., Duyvesteyn, H. M. E., Ginn, H. M., Carrique, L., Malinauskas, T., Ruza, R. R., Shah, P. N. M., Tan, T. K., Rijal, P., Coombes, N., Bewley, K. R., Tree, J. A., Radecke, J., Paterson, N. G., Supasa, P., Mongkolsapaya, J., ... Stuart, D. I. (2020). Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike. Cell Host & Microbe, 28(3), 445-e6. https://doi.org/10.1016/j.chom.2020.06.010
Huo J, et al. Neutralization of SARS-CoV-2 By Destruction of the Prefusion Spike. Cell Host Microbe. 2020 09 9;28(3):445-454.e6. PubMed PMID: 32585135.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike. AU - Huo,Jiandong, AU - Zhao,Yuguang, AU - Ren,Jingshan, AU - Zhou,Daming, AU - Duyvesteyn,Helen M E, AU - Ginn,Helen M, AU - Carrique,Loic, AU - Malinauskas,Tomas, AU - Ruza,Reinis R, AU - Shah,Pranav N M, AU - Tan,Tiong Kit, AU - Rijal,Pramila, AU - Coombes,Naomi, AU - Bewley,Kevin 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 - Townsend,Alain, AU - Fry,Elizabeth E, AU - Owens,Raymond J, AU - Stuart,David I, Y1 - 2020/06/19/ PY - 2020/05/13/received PY - 2020/05/22/revised PY - 2020/06/12/accepted PY - 2020/6/26/pubmed PY - 2020/9/22/medline PY - 2020/6/26/entrez KW - CR3022 KW - SARS-CoV-2 KW - X-ray crystallography KW - antibody KW - cryo-electron microscopy KW - epitope KW - neutralization KW - receptor binding domain KW - spike KW - therapeutic SP - 445 EP - 454.e6 JF - Cell host & microbe JO - Cell Host Microbe VL - 28 IS - 3 N2 - There are as yet no licensed therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric spike whose receptor binding domain (RBD) recognizes angiotensin-converting enzyme 2, initiating conformational changes that drive membrane fusion. We find that the monoclonal antibody CR3022 binds the RBD tightly, neutralizing SARS-CoV-2, and report the crystal structure at 2.4 Å of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilizing CR3022 epitope is inaccessible in the prefusion spike, suggesting that CR3022 binding facilitates conversion to the fusion-incompetent post-fusion state. Cryogenic electron microscopy (cryo-EM) analysis confirms that incubation of spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope could be useful therapeutically, possibly in synergy with an antibody that blocks receptor attachment. SN - 1934-6069 UR - https://www.unboundmedicine.com/medline/citation/32585135/Neutralization_of_SARS_CoV_2_by_Destruction_of_the_Prefusion_Spike_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1931-3128(20)30351-6 DB - PRIME DP - Unbound Medicine ER -