Several COVID-19 Spike protein atomistic structures in the fusion pathway are unknown
•
We use an integrative strategy combining homology-based modeling with cryo-EM fitting.
•
By adopting a 6-helix bundle, TM of the trimer is moved closer to the fusion-peptide.
•
Simulated cryo-EM maps are consistent with strong and weak experimental EM density.
•
A delta variant is positioned to increase furin cleavage of the spike protein. Omicron variants are near the fusion peptide region and in regions important for conformational changes.
Abstract
SARS-CoV-2 is the virus responsible for the COVID-19 pandemic and catastrophic, worldwide health and economic impacts. The spike protein on the viral surface is responsible for viral entry into the host cell. The binding of spike protein to the host cell receptor ACE2 is the first step leading to fusion of the host and viral membranes. Despite the vast amount of structure data that has been generated for the spike protein of SARS-CoV-2, many of the detailed structures of the spike protein in different stages of the fusion pathway are unknown, leaving a wealth of potential drug-target space unexplored. The atomic-scale structure of the complete S2 segment, as well as the complete fusion intermediate are also unknown and represent major gaps in our knowledge of the infectious pathway of SAR-CoV-2. The conformational changes of the spike protein during this process are similarly not well understood. Here we present structures of the spike protein at different stages of the fusion process. With the transitions being a necessary step before the receptor binding, we propose sites along the transition pathways as potential targets for drug development.
