Neutralisation of SARS-CoV-2 by destruction of the prefusion Spike

DOI: 10.1016/j.chom.2020.06.010

Authors: Jiandong Huo (The Wellcome Centre for Human Genetics, University of Oxford; The Rosalind Franklin Institute; Research Complex at Harwell) , Yuguang Zhao (The Wellcome Centre for Human Genetics, University of Oxford) , Jingshan Ren (The Wellcome Centre for Human Genetics, University of Oxford) , Daming Zhou (The Wellcome Centre for Human Genetics, University of Oxford) , Helen M. E. Duyvesteyn (The Wellcome Centre for Human Genetics, University of Oxford) , Helen M. Ginn (Diamond Light Source) , Loic Carrique (Wellcome Centre for Human Genetics, University of Oxford) , Tomas Malinauskas (The Wellcome Centre for Human Genetics, University of Oxford) , Reinis R. Ruza (Wellcome Centre for Human Genetics, University of Oxford) , Pranav N. M. Shah (The Wellcome Centre for Human Genetics, University of Oxford) , Tiong Kit Tan (Weatherall Institute of Molecular Medicine, University of Oxford) , Pramila Rijal (Weatherall Institute of Molecular Medicine, University of Oxford) , Naomi Coombes (Public Health England) , Kevin R. Bewley (Public Health England) , Julia A. Tree (Public Health England) , Julika Radecke (Diamond Light Source) , Neil Paterson (Diamond Light Source) , Piyasa Supasa (Wellcome Trust Centre for Human Genetics, University of Oxford) , Juthathip Mongkolsapaya (Wellcome Trust Centre for Human Genetics, University of Oxford; Mahidol University) , Gavin R. Screaton (Wellcome Trust Centre for Human Genetics, University of Oxford) , Miles Carroll (Public Health England; Wellcome Trust Centre for Human Genetics, University of Oxford) , Alain Townsend (Weatherall Institute of Molecular Medicine, University of Oxford) , Elizabeth E. Fry (The Wellcome Centre for Human Genetics, University of Oxford) , Raymond J. Owens (The Wellcome Centre for Human Genetics, University of Oxford; The Rosalind Franklin Institute; Research Complex at Harwell) , David I. Stuart (The Wellcome Centre for Human Genetics, University of Oxford; Diamond Light Source; Instruct-ERIC)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Host & Microbe

State: Published (Approved)
Published: June 2020
Diamond Proposal Number(s): 19946 , 26983

Abstract: 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) recognises angiotensin-converting enzyme 2 (ACE2), initiating conformational changes that drive membrane fusion. We find that the monoclonal antibody CR3022 binds the RBD tightly, neutralising 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-stabilising, CR3022 epitope is inaccessible in the prefusion Spike, suggesting that CR3022 binding facilitates 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.

Journal Keywords: neutralization; antibody; SARS-CoV-2; spike; receptor binding domain; epitope; therapeutic; CR3022; cryo-electron microscopy; X-ray crystallography

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: 24/06/2020 08:45

Documents:
1-s2.0-S1931312820303516-main-2.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)