The SARS-CoV-2 spike reversibly samples an open-trimer conformation exposing novel epitopes

Area of Science:

• Structural biology
• Virology
• Immunology

Background:

• Current COVID-19 vaccines and diagnostics rely on the SARS-CoV-2 spike ectodomain.
• Understanding the full conformational landscape of the spike protein is crucial for developing effective countermeasures.

Purpose of the Study:

• To investigate alternative conformations of the SARS-CoV-2 spike ectodomain beyond the known prefusion structure.
• To characterize the structural features and accessibility of this newly identified conformation.

Main Methods:

• Hydrogen-deuterium exchange monitored by mass spectrometry (HDX-MS).
• Comparison with existing cryo-electron microscopy (cryo-EM) data for the prefusion structure.

Main Results:

• A novel, slowly interconverting "open trimer" conformation of the spike protein was identified.
• This open conformation features accessible receptor-binding domains and exposes the conserved trimer interface.
• The population and dynamics of this state are influenced by temperature, receptor/antibody binding, and viral variants.

Conclusions:

• The newly discovered open trimer conformation presents new potential epitopes for pan-coronavirus recognition.
• Understanding this alternative state can guide the design of improved diagnostics, therapeutics, and vaccines against SARS-CoV-2 and related coronaviruses.