The antigenic anatomy of SARS-CoV-2 receptor binding domain

DOI: 10.1016/j.cell.2021.02.032

Authors: Wanwisa Dejnirattisai (The Wellcome Centre for Human Genetic, University of Oxford) , Daming Zhou (The Wellcome Centre for Human Genetics, University of Oxford) , Helen M. Ginn (The Wellcome Centre for Human Genetic, University of Oxford) , Helen M. E. Duyvesteyn (The Wellcome Centre for Human Genetics, University of Oxford) , Piyada Supasa (The Wellcome Centre for Human Genetic, University of Oxford) , James Brett Case (Washington University School of Medicine) , Yuguang Zhao (The Wellcome Centre for Human Genetic, University of Oxford) , Thomas Walter (The Wellcome Centre for Human Genetic, University of Oxford) , Alexander J. Mentzer (The Wellcome Centre for Human Genetic, University of Oxford) , Chang Liu (The Wellcome Centre for Human Genetic, University of Oxford; Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford) , Beibei Wang (The Wellcome Centre for Human Genetic, University of Oxford) , Guido C. Paesen (The Wellcome Centre for Human Genetic, University of Oxford) , Jose Slon-Campos (The Wellcome Centre for Human Genetic, University of Oxford) , César López-Camacho (The Wellcome Centre for Human Genetic, University of Oxford) , Natasha M. Kafai (Washington University School of Medicine) , Adam L. Bailey (Washington University School of Medicine) , Rita E. Chen (Washington University School of Medicine) , Baoling Ying (Washington University School of Medicine) , Craig Thompson (University of Oxford) , Jai Bolton (University of Oxford) , Alex Fyfe (University of Oxford) , Sunetra Gupta (University of Oxford) , Tiong Kit Tan (University of Oxford) , Javier Gilbert-Jaramillo (University of Oxford) , William James (University of Oxford) , Michael Knight (University of Oxford) , Miles W. Carroll (University of Oxford; Public Health England (PHE)) , Donal Skelly (Oxford University Hospitals NHS Foundation Trust; University of Oxford) , Christina Dold (University of Oxford; NIHR Oxford Biomedical Research Centre) , Yanchun Peng (University of Oxford) , Robert Levin (Worthing Hospital) , Tao Dong (Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford) , Andrew J. Pollard (Oxford University Hospitals NHS Foundation Trust; University of Oxford; NIHR Oxford Biomedical Research Centre) , Julian C. Knight (The Wellcome Centre for Human Genetic, University of Oxford; Oxford University Hospitals NHS Foundation Trust) , Paul Klenerman (Oxford University Hospitals NHS Foundation Trust; NIHR Oxford Biomedical Research Centre; University of Oxford) , Nigel Temperton (University of Kent) , David R. Hall (Diamond Light Source) , Mark A. Williams (Diamond Light Source) , Neil G. Paterson (Diamond Light Source) , Felicity Bertram (Diamond Light Source) , C. Alistair Siebert (Diamond Light Source) , Daniel K. Clare (Diamond Light Source) , Andrew Howe (Diamond Light Source) , Julika Radecke (Diamond Light Source) , Yun Song (Diamond Light Source) , Alain R. Townsend (Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford) , Kuan-Ying A. Huang (Chang Gung University; Chang Gung Memorial Hospital) , Elizabeth E. Fry (The Wellcome Centre for Human Genetic, University of Oxford) , Juthathip Mongkolsapaya (The Wellcome Centre for Human Genetic, University of Oxford; Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford; Mahidol University) , Michael S. Diamond (Washington University School of Medicine) , Jingshan Ren (The Wellcome Centre for Human Genetics, University of Oxford) , David I. Stuart (The Wellcome Centre for Human Genetic, University of Oxford; Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford; Diamond Light Source; Instruct-ERIC) , Gavin R. Screaton (The Wellcome Centre for Human Genetic, University of Oxford; Oxford University Hospitals NHS Foundation Trust)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell

State: Published (Approved)
Published: February 2021
Diamond Proposal Number(s): 27009 , 26983

Abstract: Antibodies are crucial to immune protection against SARS-CoV-2, with some in emergency use as therapeutics. Here we identify 377 human monoclonal antibodies (mAbs) recognizing the virus spike, and focus mainly on 80 that bind the receptor binding domain (RBD). We devise a competition data driven method to map RBD binding sites. We find that although antibody binding sites are widely dispersed, neutralizing antibody binding is focused, with nearly all highly inhibitory mAbs (IC50<0.1μg/ml) blocking receptor interaction, except for one that binds a unique epitope in the N-terminal domain. Many of these neutralizing mAbs use public V-genes and are close to germline. We dissect the structural basis of recognition for this large panel of antibodies through X-ray crystallography and cryo-electron microscopy of 19 Fab-antigen structures. We find novel binding modes for some potently inhibitory antibodies and demonstrate that strongly neutralizing mAbs protect, prophylactically or therapeutically, in animal models.

Diamond Keywords: COVID-19; Viruses

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: I03-Macromolecular Crystallography , Krios I-Titan Krios I at Diamond

Added On: 24/02/2021 09:23

Documents:
1-s2.0-S009286742100221X-main.pdf

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Microscopy Macromolecular Crystallography (MX) Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)