Abstract
Substitution for aspartic acid (D) by glycine (G) at position 614 in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears to facilitate rapid viral spread. The G614 strain and its recent variants are now the dominant circulating forms. Here, we report cryo-electron microscopy structures of a full-length G614 S trimer, which adopts three distinct prefusion conformations that differ primarily by the position of one receptor-binding domain. A loop disordered in the D614 S trimer wedges between domains within a protomer in the G614 spike. This added interaction appears to prevent premature dissociation of the G614 trimer-effectively increasing the number of functional spikes and enhancing infectivity-and to modulate structural rearrangements for membrane fusion. These findings extend our understanding of viral entry and suggest an improved immunogen for vaccine development.
Highlights
receptor-binding domain (RBD)-angiotensin converting enzyme 2 (ACE2) complexes (14–17), and segments of S2 in the postfusion state (18)
First release: 16 March 2021 www.sciencemag.org (Page numbers not final at time of first release) 1 the RBD-up conformations more frequently than does the D614 trimer (13, 29, 32), but it is puzzling why the former binds more weakly to recombinant ACE2 than the latter (32)
The known S trimer structures indicate that the D614G change breaks a salt bridge between D614 and a lysine residue (K854) in the fusion peptide proximal region (FPPR) (19, 33, 34), which may help clamp the RBD in the prefusion conformation
Summary
RBD-ACE2 complexes (14–17), and segments of S2 in the postfusion state (18). In the prefusion ectodomain structure, S1 folds into four domains - NTD (N-terminal domain), RBD, and two CTDs (C-terminal domains), and wraps around the prefusion S2, with the RBD sampling two distinct conformations – “up” for a receptor-accessible state and “down” for a receptor-inaccessible state. We and others have reported structures of a purified, full-length D614 S protein in both prefusion and postfusion conformations (19, 20). The overall structure of the G614 S protein in the closed, three RBD-down prefusion conformation is very similar to that of our published D614 S trimer (Fig. 2) (19). Our interpretation of the structural differences is www.sciencemag.org (Page numbers not final at time of first release) 3 consistent with the spike conformational distribution on the virions in cryo-ET studies of chemically inactivated SARSCoV-2.
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