@article{91464e7e0a1246e2a0837091283f7f19,
title = "SARS-CoV-2 can recruit a heme metabolite to evade antibody immunity",
abstract = "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.",
author = "Annachiara Rosa and Pye, {Valerie E} and Carl Graham and Luke Muir and Jeffrey Seow and Ng, {Kevin W} and Cook, {Nicola J} and Chloe Rees-Spear and Eleanor Parker and {Silva Dos Santos}, Mariana and Carolina Rosadas and Alberto Susana and Hefin Rhys and Andrea Nans and Laura Masino and Chloe Roustan and Evangelos Christodoulou and Rachel Ulferts and Wrobel, {Antoni G} and Charlotte-Eve Short and Michael Fertleman and Sanders, {Rogier W} and Judith Heaney and Moira Spyer and Svend Kj{\ae}r and Andy Riddell and Malim, {Michael H} and Rupert Beale and MacRae, {James I} and Taylor, {Graham P} and Eleni Nastouli and {van Gils}, {Marit J} and Rosenthal, {Peter B} and Massimo Pizzato and McClure, {Myra O} and Tedder, {Richard S} and George Kassiotis and McCoy, {Laura E} and Doores, {Katie J} and Peter Cherepanov",
note = "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 {\textcopyright} 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).",
year = "2021",
month = may,
doi = "10.1126/sciadv.abg7607",
language = "English",
volume = "7",
journal = "Science Advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "22",
}
