Mapping antibody recognition of SARS-CoV-2 spike protein

Authors: Jingshan Ren (University of Oxford, Diamond Light Source) , David I. Stuart (University of Oxford; Diamond Light Source)
Co-authored by industrial partner: No

Type: Diamond Annual Review Highlight

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

Abstract: The COVID-19 vaccines currently in use in Europe and the USA aim to generate antibodies against the virus spike. We need to know where these antibodies bind and how they neutralise the virus. Viruses mutate to escape antibody binding, and changes to the spike structure can stop antibody attachment. An international team of researchers identified 377 human monoclonal antibodies (mAbs) from recovered SARS-CoV-2 patients that recognised the virus spike. They used cryo-electron microscopy (cryo-EM) at the Electron Bio-Imaging Centre (eBIC) and Macromolecular Crystallography (MX) on beamline I03 at Diamond Light Source to investigate the complex structures of the SARS-CoV-2 spike or the receptor binding domain (RBD) with the antibody Fabs (a region on an antibody that binds to antigens). The team determined the structures of 11 spike/Fab complexes by cryo-EM and 18 RBD/fab complexes by crystallography. Using a combination of structural methods, and a novel computational algorithm utilising competition bio-layer interferometry data, they localised binding epitopes of 80 on the surface of the RBD. Three of the potent neutralising mAbs are glycosylated, and the glycans contribute to neutralisation. Their results identify the precise binding sites on the spike and their detailed interactions. This information can guide combinations for antibody cocktail therapy. More potent neutralising monoclonal antibodies (mABs) can be designed through structural analysis. Understanding how the binding of these antibodies is affected in variant viruses is helpful in understanding how we might design next- generation vaccines. The project involved many groups working closely together, and success in such a difficult time was only possible due to tremendous support and collaboration with eBIC, the Oxford Particle Imaging Centre (OPIC) and I03.

Journal Keywords: SARS-CoV-2; Antibody; Germline; V-gene; Receptor-binding-domain; Spike; Neutralisation; Protection; Glycosylation

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: 12/11/2021 11:23

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)