Figure 2. SARS-CoV-2 spike (S) glycoprotein.

A. The S protein includes (i) the trimeric S1 subunit, which contains 3 receptor-binding domains (RBDs) (two of which are lying down, with one standing up); (ii) the membrane-associated S2 subunit, which includes a fusion peptide; (iii) a transmembrane (TM) anchor and (iv) an intracellular tail.⁶⁰ B. Schematic to show the early stage of viral uptake.⁶⁰ Viral uptake commences with proteolytic cleavage by furin, which separates the S1 and S2 subunits, enabling one RBD to stand up. Next, the 2nd and then the 3rd RBD domains stand up. The achievement of a pre-fusion complex (with 3 RBDs standing up) leads to two important outcomes: (i) exposure and immune recognition of S1 epitopes that were covered up by the RBDs in the lying down conformation; (ii) high affinity binding of RBDs to the host hACE2 receptor to enable viral docking. Once docked onto the host cell membrane, the contraction of the S2 fusion peptide blends the viral envelope with the host cell membrane. Adapted with permission from ref 60 under a Creative Commons Attribution License 4.0 (CC BY). Copyright 2020 The Authors.