The Francis Crick Institute
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SARS-CoV-2 can recruit a haem metabolite to evade antibody immunity

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journal contribution
posted on 2021-06-16, 10:45 authored by Annachiara Rosa, Valerie E Pye, Carl Graham, Luke Muir, Jeffrey Seow, Kevin W Ng, Nicola J Cook, Chloe Rees-Spear, Eleanor Parker, Mariana Silva Dos Santos, Carolina Rosadas, Alberto Susana, Hefin Rhys, Andrea Nans, Laura Masino, Chloe Roustan, Evangelos Christodoulou, Rachel Ulferts, Antoni G Wrobel, Charlotte-Eve Short, Michael Fertleman, Rogier W Sanders, Judith Heaney, Moira Spyer, Svend Kjaer, Andy Riddell, Michael H Malim, Rupert Beale, James I MacRae, Graham P Taylor, Eleni Nastouli, Marit J van Gils, Peter B Rosenthal, Massimo Pizzato, Myra O McClure, Richard S Tedder, George Kassiotis, Laura E Mccoy, Katie J Doores, Peter Cherepanov
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.


Crick (Grant ID: 10827, Grant title: Beale FC001827) Crick (Grant ID: 10061, Grant title: Cherepanov FC001061) Crick (Grant ID: 10099, Grant title: Kassiotis FC001099) Crick (Grant ID: 10143, Grant title: Rosenthal FC001143) Crick (Grant ID: 10006, Grant title: STP Flow Cytometry) Crick (Grant ID: 10012, Grant title: STP Metabolomics) Crick (Grant ID: 10015, Grant title: STP Structural Biology)