A Cryptic Site of Vulnerability on the Receptor Binding Domain of the SARS-CoV-2 Spike Glycoprotein
A Cryptic Site of Vulnerability on the Receptor Binding Domain of the SARS-CoV-2 Spike Glycoprotein
SUMMARY SARS-CoV-2 is a zoonotic virus that has caused a pandemic of severe respiratory disease—COVID-19— within several months of its initial identification. Comparable to the first SARS-CoV, this novel coronavirus’s surface Spike (S) glycoprotein mediates cell entry via the human ACE-2 receptor, and, thus, is the principal target for the development of vaccines and immunotherapeutics. Molecular information on the SARS-CoV-2 S glycoprotein remains limited. Here we report the crystal structure of the SARS-CoV-2 S receptor-binding-domain (RBD) at a the highest resolution to date, of 1.95 ?. We identified a set of SARS-reactive monoclonal antibodies with cross-reactivity to SARS-CoV-2 RBD and other betacoronavirus S glycoproteins. One of these antibodies, CR3022, was previously shown to synergize with antibodies that target the ACE-2 binding site on the SARS-CoV RBD and reduce viral escape capacity. We determined the structure of CR3022, in complex with the SARS-CoV-2 RBD, and defined a broadly reactive epitope that is highly conserved across betacoronaviruses. This epitope is inaccessible in the “closed” prefusion S structure, but is accessible in “open” conformations. This first-ever resolution of a human antibody in complex with SARS-CoV-2 and the broad reactivity of this set of antibodies to a conserved betacoronavirus epitope will allow antigenic assessment of vaccine candidates, and provide a framework for accelerated vaccine, immunotherapeutic and diagnostic strategies against SARS-CoV-2 and related betacoronaviruses. HIGHLIGHTSHigh resolution structure of the SARS-CoV-2 Receptor-Binding-Domain (RBD).Recognition of the SARS-CoV-2 RBD by SARS-CoV antibodies.Structure of the SARS-COV-2 RBD in complex with antibody CR3022.Identification of a cryptic site of vulnerability on the SARS-CoV-2 Spike.
Sterling Spencer L.、de Val Natalia、Scott Paul、Rolland Morgane、Chen Wei-Hung、Green Ethan C.、Yan Lianying、Choe Misook、Broder Christopher C.、Peterson Caroline E.、Amare Mihret、Laing Eric D.、Michael Nelson L.、Smith Clayton、Sankhala Rajeshwer S.、Hajduczki Agnes、Bai Hongjun、Modjarrad Kayvon、Joyce M. Gordon
Department of Microbiology and Immunology, Uniformed Services UniversityCenter for Molecular Microscopy, Center for Cancer Research, National Cancer Institute, National Institutes of Health||Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc.Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research||Center for Infectious Diseases Research, Walter Reed Army Institute of ResearchEmerging Infectious Diseases Branch, Walter Reed Army Institute of Research||U.S. Military HIV Research Program, Walter Reed Army Institute of Research||Henry M. Jackson Foundation for the Advancement of Military Medicine||Center for Infectious Diseases Research, Walter Reed Army Institute of ResearchEmerging Infectious Diseases Branch, Walter Reed Army Institute of Research||U.S. Military HIV Research Program, Walter Reed Army Institute of Research||Henry M. Jackson Foundation for the Advancement of Military Medicine||Center for Infectious Diseases Research, Walter Reed Army Institute of ResearchEmerging Infectious Diseases Branch, Walter Reed Army Institute of Research||Department of Microbiology and Immunology, Uniformed Services University||Center for Infectious Diseases Research, Walter Reed Army Institute of ResearchDepartment of Microbiology and Immunology, Uniformed Services UniversityEmerging Infectious Diseases Branch, Walter Reed Army Institute of Research||U.S. Military HIV Research Program, Walter Reed Army Institute of Research||Henry M. Jackson Foundation for the Advancement of Military Medicine||Center for Infectious Diseases Research, Walter Reed Army Institute of ResearchDepartment of Microbiology and Immunology, Uniformed Services UniversityEmerging Infectious Diseases Branch, Walter Reed Army Institute of Research||U.S. Military HIV Research Program, Walter Reed Army Institute of Research||Henry M. Jackson Foundation for the Advancement of Military Medicine||Center for Infectious Diseases Research, Walter Reed Army Institute of ResearchEmerging Infectious Diseases Branch, Walter Reed Army Institute of Research||Henry M. Jackson Foundation for the Advancement of Military Medicine||Center for Infectious Diseases Research, Walter Reed Army Institute of ResearchDepartment of Microbiology and Immunology, Uniformed Services UniversityCenter for Infectious Diseases Research, Walter Reed Army Institute of ResearchCenter for Molecular Microscopy, Center for Cancer Research, National Cancer Institute, National Institutes of Health||Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc.Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research||U.S. Military HIV Research Program, Walter Reed Army Institute of Research||Henry M. Jackson Foundation for the Advancement of Military Medicine||Center for Infectious Diseases Research, Walter Reed Army Institute of ResearchEmerging Infectious Diseases Branch, Walter Reed Army Institute of Research||U.S. Military HIV Research Program, Walter Reed Army Institute of Research||Henry M. Jackson Foundation for the Advancement of Military Medicine||Center for Infectious Diseases Research, Walter Reed Army Institute of ResearchEmerging Infectious Diseases Branch, Walter Reed Army Institute of Research||U.S. Military HIV Research Program, Walter Reed Army Institute of Research||Henry M. Jackson Foundation for the Advancement of Military Medicine||Center for Infectious Diseases Research, Walter Reed Army Institute of ResearchEmerging Infectious Diseases Branch, Walter Reed Army Institute of Research||Center for Infectious Diseases Research, Walter Reed Army Institute of ResearchEmerging Infectious Diseases Branch, Walter Reed Army Institute of Research||U.S. Military HIV Research Program, Walter Reed Army Institute of Research||Henry M. Jackson Foundation for the Advancement of Military Medicine||Center for Infectious Diseases Research, Walter Reed Army Institute of Research
基础医学生物科学研究方法、生物科学研究技术分子生物学
CoronavirusCOVID-19SARS-CoV-2AntibodiesPandemicStructural BiologyReceptor-Binding-Domain
Sterling Spencer L.,de Val Natalia,Scott Paul,Rolland Morgane,Chen Wei-Hung,Green Ethan C.,Yan Lianying,Choe Misook,Broder Christopher C.,Peterson Caroline E.,Amare Mihret,Laing Eric D.,Michael Nelson L.,Smith Clayton,Sankhala Rajeshwer S.,Hajduczki Agnes,Bai Hongjun,Modjarrad Kayvon,Joyce M. Gordon.A Cryptic Site of Vulnerability on the Receptor Binding Domain of the SARS-CoV-2 Spike Glycoprotein[EB/OL].(2025-03-28)[2025-07-09].https://www.biorxiv.org/content/10.1101/2020.03.15.992883.点此复制
评论