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.
Highlights
Trimeric coronaviral spike glycoproteins form prominent features on viral particles that are responsible for the attachment to a receptor on the host cell and, fusion of the viral and cellular membranes [1, 2]
SARS-CoV-2 and SARS-CoV-1 spike Nterminal domain (NTD) bind biliverdin and bilirubin In the course of our activities to support the development of serology for SARS-CoV-2, we produced a range of
We isolated the pigment from denatured SARS-CoV-2 S1 and confirmed the presence of biliverdin IXα by mass spectrometry
Summary
Trimeric coronaviral spike glycoproteins form prominent features on viral particles that are responsible for the attachment to a receptor on the host cell and, fusion of the viral and cellular membranes [1, 2]. The recognition of the betacoronavirus SARS-CoV-2 host receptor, the cellular membrane protein angiotensin-converting enzyme 2 (ACE2), maps to the S1 C-terminal domain (referred to as the receptor binding domain, RBD) [3,4,5], while the function of the Nterminal domain (NTD) remains enigmatic. The immune properties of the spike glycoprotein underpin ongoing SARSCoV-2 vaccine development efforts [6]. Both S1 domains can be targeted by potent neutralizing antibodies that arise in infected individuals. Mutations within the SARS-CoV-2 spike NTD are associated with viral escape from antibody immunity [12,13,14] and have been observed in circulating viral strains [15, 16]
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