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Entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells depends on refolding of the virus-encoded spike protein from a prefusion conformation, metastable after cleavage, to a lower energy, stable postfusion conformation. This transition overcomes kinetic barriers for fusion of viral and target cell membranes. We report here a cryo-EM structure of the intact postfusion spike in a lipid bilayer that represents single-membrane product of the fusion reaction. The structure provides structural definition of the functionally critical membrane-interacting segments, including the fusion peptide and transmembrane anchor. The internal fusion peptide forms a hairpin-like wedge that spans almost the entire lipid bilayer and the transmembrane segment wraps around the fusion peptide at the last stage of membrane fusion. These results advance our understanding of the spike protein in a membrane environment and may guide development of intervention strategies.

Significance Epstein–Barr virus (EBV) contributes to Burkitt lymphoma and post-transplant lymphoproliferative disease (PTLD). EBV-transforming programs activate lipid metabolism to convert B cells into immortalized lymphoblastoid cell lines (LCL), a PTLD model. We found that stages of EBV transformation generate lipid reactive oxygen species (ROS) byproducts to varying degrees, and that a Burkitt-like phase of B cell outgrowth requires lipid ROS detoxification by glutathione peroxidase 4 and its cofactor glutathione. Perturbation of this redox defense in early stages of transformation or in Burkitt cells triggered ferroptosis, a programmed cell death pathway. LCLs were less dependent on this defense, a distinction tied to EBV latency programs. This highlights ferroptosis induction as a potential therapeutic approach for prevention or treatment of certain EBV+ lymphomas.