Abstract
| Original language | English |
|---|---|
| Article number | eabg7607 |
| Journal | Science advances |
| Volume | 7 |
| Issue number | 22 |
| DOIs | |
| Publication status | Published - 1 May 2021 |
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In: Science advances, Vol. 7, No. 22, eabg7607, 01.05.2021.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - SARS-CoV-2 can recruit a heme metabolite to evade antibody immunity
AU - Rosa, Annachiara
AU - Pye, Valerie E.
AU - Graham, Carl
AU - Muir, Luke
AU - Seow, Jeffrey
AU - Ng, Kevin W.
AU - Cook, Nicola J.
AU - Rees-Spear, Chloe
AU - Parker, Eleanor
AU - dos Santos, Mariana Silva
AU - Rosadas, Carolina
AU - Susana, Alberto
AU - Rhys, Hefin
AU - Nans, Andrea
AU - Masino, Laura
AU - Roustan, Chloe
AU - Christodoulou, Evangelos
AU - Ulferts, Rachel
AU - Wrobel, Antoni G.
AU - Short, Charlotte-Eve
AU - Fertleman, Michael
AU - Sanders, Rogier W.
AU - Heaney, Judith
AU - Spyer, Moira
AU - Kjær, Svend
AU - Riddell, Andy
AU - Malim, Michael H.
AU - Beale, Rupert
AU - MacRae, James I.
AU - Taylor, Graham P.
AU - Nastouli, Eleni
AU - van Gils, Marit J.
AU - Rosenthal, Peter B.
AU - Pizzato, Massimo
AU - McClure, Myra O.
AU - Tedder, Richard S.
AU - Kassiotis, George
AU - McCoy, Laura E.
AU - Doores, Katie J.
AU - Cherepanov, Peter
N1 - Funding Information: This research was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust. Work in P.C. laboratory was additionally supported by U.S. National Institutes of Health grant P50 AI150481. The project was also funded by the King's Together Rapid COVID-19 Call award (to K.J.D. and M.H.M.), the Huo Family Foundation (to M.H.M. and K.J.D.), and by the UCL Coronavirus Response Fund made possible through generous donations from UCL's supporters, alumni, and friends (to L.E.M. and L.Mu.). Flow cytometry was supported by a multi-user equipment grant from The Wellcome Trust to M.H.M. and K.J.D. (208354/Z/17/Z). L.E.M. is supported by a Medical Research Council Career Development Award (MR/R008698/1). M.J.v.G. is a recipient of an AMC Fellowship, and R.W.S. is a recipient of a Vici grant from the Netherlands Organization for Scientific Research (NWO). C.G. was supported by the MRC-KCL Doctoral Training Partnership in Biomedical Sciences (MR/N013700/1). M.O.M., E.P., and R.S.T. were supported in part by an UKRI/MRC Covid-19 grant (MC_PC_19078). E.N., M.J.S., and J.H. received support from the UKRI COVID-19 research scheme. This study is part of the EDCTP2 program supported by the European Union (grant number RIA2020EF-3008 COVAB) (to K.J.D. and M.H.M.). The views and opinions of authors expressed here do not necessarily state or reflect those of EDCTP. This work was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001061, FC001065, FC001099, FC001827, FC001078), the UK Medical Research Council (FC001061, FC001065, FC001099, FC001827, FC001078), and the Wellcome Trust (FC001061, FC001065, FC001099, FC001827, FC001078). For the purpose of Open Access, the author has applied a CC BY public copyright license to any author accepted manuscript version arising from this submission. Publisher Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
PY - 2021/5/1
Y1 - 2021/5/1
N2 - The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of heme metabolism, with nanomolar affinity. Using cryo-electron microscopy and x-ray crystallography, we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that SARS-CoV-2 spike NTD harbors a dominant epitope, access to which can be controlled by an allosteric mechanism that is regulated through recruitment of a metabolite.
AB - The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of heme metabolism, with nanomolar affinity. Using cryo-electron microscopy and x-ray crystallography, we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that SARS-CoV-2 spike NTD harbors a dominant epitope, access to which can be controlled by an allosteric mechanism that is regulated through recruitment of a metabolite.
UR - http://www.scopus.com/inward/record.url?scp=85107010557&partnerID=8YFLogxK
U2 - https://doi.org/10.1126/sciadv.abg7607
DO - https://doi.org/10.1126/sciadv.abg7607
M3 - Article
C2 - 33888467
SN - 2375-2548
VL - 7
JO - Science advances
JF - Science advances
IS - 22
M1 - eabg7607
ER -