A triggering structure of SARS-CoV-2 BA.2.86 spike upon ACE2 binding for receptor-binding domain up (preprint)

ABSTRACT

Since 2019, SARS-CoV-2 has undergone mutations, resulting in pandemic and epidemic waves. The SARS-CoV-2 spike protein, crucial for cellular entry, is believed to bind to the ACE2 receptor exclusively when its receptor-binding domain (RBD) adopts the “up” conformation. However, whether ACE2 exclusively binds to the “up” RBD or also interacts with the “down” RBD to facilitate the conformational shift to RBD-up remains unclear. Here, we present the structures of the BA.2.86 spike alone and bound to ACE2. The N354-linked glycan contributes to the neutralizing antibody evasion in BA.2.86. Notably, we successfully observed the ACE2-bound “down” RBD, indicating a trigger structure before the RBD-up conformation. The wider and mobile angle of RBDs in the “up” state provides space for ACE2 to interact with the “down” RBD, facilitating the transition to the RBD-up state. These structural insights into the spike-protein dynamics would help understand the mechanisms underlying SARS-CoV-2 infection and its neutralization.