| Background |
2019-nCoV makes use of a densely glycosylated, homotrimeric class I fusion spike (S) protein to gain entry into host cells. The S protein exists in a metastable prefusion conformation that undergoes a dramatic structural rearrangement to fuse the viral membrane with the host cell membrane. This process is triggered by binding of the S1 subunit to a host-cell receptor ACE2, which destabilizes the prefusion trimer, resulting in shedding of the S1 subunit and transition of the S2 subunit to a highly stable postfusion conformation. In order to engage a host-cell receptor, the receptor-binding domain (RBD) of S1 undergoes hinge-like conformational movements that transiently hide or expose the determinants of receptor binding. These two states are referred to as the “down” conformation and the “up” conformation, where “down” corresponds to the receptor-inaccessible state and “up” corresponds to the receptor-accessible state, which is thought to be less stable. Due to the indispensable function of the S protein it represents a vulnerable target for antibody-mediated neutralization, and characterization of the prefusion S structure would provide atomic-level information to guide vaccine design and development. |
