Up, up, down, down: the structural biology of the SARS-CoV-2 spike protein and how it cheats the immune system

Spike proteins protrude from the SARS-CoV-2 viral envelope and are responsible for initiating fusion into human epithelial cells by binding Angiotensin-Converting Enzyme 2 receptors on the host cell surface. Due to their exposed location on the outside of the virion and their key role in infection, SARS-CoV-2 spike proteins are an important target for vaccine development and drug design. Over the last two years, many spike protein structures have been experimentally determined, providing essential details into the complex structural rearrangements that occur after receptor binding and during fusion of the virion with the host cell, as well as into the interactions of spike protein molecules with antibodies. SARS-CoV-2 variants, particularly those associated with reduced vaccine efficacy, are strongly associated with mutations in two domains of the SARS-CoV-2 spike protein, namely the receptor binding domain and the N-terminal domain, which have both been structurally characterized. This review provides a comprehensive overview of the structural knowledge acquired over the past four years on the SARS-CoV-2 spike protein and its critical role in viral infection.