Neutralization of SARS-CoV-2 by destruction of the prefusion Spike
Neutralization of SARS-CoV-2 by destruction of the prefusion Spike
Summary There are as yet no licenced 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 (ACE2), initiating conformational changes that drive membrane fusion. We find that monoclonal antibody CR3022 binds the RBD tightly, neutralising SARS-CoV-2 and report the crystal structure at 2.4 ? of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilising, CR3022 epitope is inaccessible in the prefusion Spike, suggesting that CR3022 binding would facilitate conversion to the fusion-incompetent post-fusion state. 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 may be useful therapeutically, possibly in synergy with an antibody blocking receptor attachment. HighlightsCR3022 neutralises SARS-CoV-2Neutralisation is by destroying the prefusion SPIKE conformationThis antibody may have therapeutic potential alone or with one blocking receptor attachment
Mongkolsapaya Juthathip、Carrique Loic、Ren Jingshan、Zhou Daming、Duyvesteyn Helen ME、Ginn Helen M、Ruza Reinis R、Rijal Pramila、Bewley Kevin、Paterson Neil G、Townsend Alain、Fry Elizabeth E、Supasa Piyasa、Screaton Gavin R、Tan Tiong Kit、Coombes Naomi、Owens Raymond J、Zhao Yuguang、Malinauskas Tomas、Carroll Miles、Stuart David I、Radecke Julika、Huo Jiandong、Shah Pranav NM
Nuffield Department of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford||Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol UniversityDivision of Structural Biology, University of Oxford, The Wellcome Centre for Human GeneticsDivision of Structural Biology, University of Oxford, The Wellcome Centre for Human GeneticsDivision of Structural Biology, University of Oxford, The Wellcome Centre for Human GeneticsDivision of Structural Biology, University of Oxford, The Wellcome Centre for Human GeneticsDiamond Light Source Ltd, Harwell Science & Innovation CampusDivision of Structural Biology, University of Oxford, The Wellcome Centre for Human GeneticsMRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe HospitalNational Infection Service, Public Health EnglandDiamond Light Source Ltd, Harwell Science & Innovation CampusMRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe HospitalDivision of Structural Biology, University of Oxford, The Wellcome Centre for Human GeneticsNuffield Department of Medicine, Wellcome Trust Centre for Human Genetics, University of OxfordNuffield Department of Medicine, Wellcome Trust Centre for Human Genetics, University of OxfordMRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe HospitalNational Infection Service, Public Health EnglandDivision of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics||The Rosalind Franklin Institute||Protein Production UK, Research Complex at Harwell, Harwell Science & Innovation CampusDivision of Structural Biology, University of Oxford, The Wellcome Centre for Human GeneticsDivision of Structural Biology, University of Oxford, The Wellcome Centre for Human GeneticsNational Infection Service, Public Health England||Nuffield Department of Medicine, Wellcome Trust Centre for Human Genetics, University of OxfordDivision of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics||Diamond Light Source Ltd, Harwell Science & Innovation CampusDiamond Light Source Ltd, Harwell Science & Innovation CampusDivision of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics||The Rosalind Franklin Institute||Protein Production UK, Research Complex at Harwell, Harwell Science & Innovation CampusDivision of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics
基础医学生物科学研究方法、生物科学研究技术生物化学
Mongkolsapaya Juthathip,Carrique Loic,Ren Jingshan,Zhou Daming,Duyvesteyn Helen ME,Ginn Helen M,Ruza Reinis R,Rijal Pramila,Bewley Kevin,Paterson Neil G,Townsend Alain,Fry Elizabeth E,Supasa Piyasa,Screaton Gavin R,Tan Tiong Kit,Coombes Naomi,Owens Raymond J,Zhao Yuguang,Malinauskas Tomas,Carroll Miles,Stuart David I,Radecke Julika,Huo Jiandong,Shah Pranav NM.Neutralization of SARS-CoV-2 by destruction of the prefusion Spike[EB/OL].(2025-03-28)[2025-05-11].https://www.biorxiv.org/content/10.1101/2020.05.05.079202.点此复制
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