Conformational dynamics of SARS-CoV-2 trimeric spike glycoprotein in complex with receptor ACE2 revealed by cryo-EM.

The recent outbreaks and rapid international spread of SARS-CoV-2 pose a global health emergency. Its trimeric spike (S) glycoprotein interacts with human ACE2-receptor to mediate viral entry into host-cells. Here we present cryo-EM structures of a tightly closed SARS-CoV-2 S-trimer with packed fusion peptide, and an ACE2-bound S-trimer at 2.7 Å and 3.8 Å resolution, respectively. Accompanying ACE2 binding to the up receptor-binding domain (RBD), the associated ACE2-RBD exhibits continuous swing-motions within the S-trimer. Noteworthy, SARS-CoV-2 S-trimer appears much more sensitive to ACE2-receptor than SARS-CoV S-trimer regarding receptor-triggered transformation from the closed prefusion state to fusion-prone open state, potentially contributing to the superior infectivity of SARS-CoV-2. We defined the RBD T470-T478 loop and Y505 as viral determinants for specific recognition of SARS-CoV-2 RBD by ACE2. Our findings depict the mechanism of ACE2-induced S-trimer conformational transitions from ground prefusion state toward postfusion state, facilitating development of anti-SARS-CoV-2 vaccines and therapeutics.