Snapshots from Cryo-ET of active SARS-CoV-2 virions

Understanding the molecular properties of SARS-CoV-2 is crucial to tackle the continuing variant emergence as well as future outbreaks. Current structural knowledge of the trimeric spike protein is largely based on truncated recombinant proteins and inactivated full-length forms, which may suffer from overstabilization through designed mutations and chemical fixation. Here, we apply cryo-electron tomography (cryo-ET) at a Biosafety level 3 facility to study the virus structure in its native, active state. The virus particles show variable shapes with diffusible spikes. While the majority of spike proteins display typical prefusion trimer conformations, we identify atypical open-trimer prefusion states, revealing a hidden level of flexibility. The sub-tomogram averaged structure also suggests a loosely packed trimer structure. Spike dynamics reveal cryptic epitopes in conserved regions among coronaviruses that can be targeted for broadly effective vaccines. Therefore, the structural analysis of virus structures in their active forms will provide significant implications on fusion mechanism as well as vaccine and antibody/drug design. ### Competing Interest Statement The authors have declared no competing interest.