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

The recent outbreaks of SARS-CoV-2 pose a global health emergency. The SARS-CoV-2 trimeric spike (S) glycoprotein interacts with the human ACE2 receptor to mediate viral entry into host cells. We report the 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- and 3.8- A resolution, respectively. Accompanying ACE2 binding to the up receptor-binding domain ( RBD), the associated ACE2-RBD exhibits continuous swing motions. Notably, the SARS-CoV-2 S trimer appears much more sensitive to the ACE2 receptor than the SARS-CoV S trimer regarding receptor-triggered transformation from the closed prefusion state to the 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 the ground prefusion state toward the postfusion state, facilitating development of anti-SARS-CoV-2 vaccines and therapeutics.

Automated summary

The recent global health emergency caused by SARS-CoV-2 outbreak is mediated by the interaction between the SARS-CoV-2 trimeric spike glycoprotein and the human ACE2 receptor. The SARS-CoV-2 S trimer is more sensitive to ACE2 receptor compared to SARS-CoV S trimer, potentially contributing to its superior infectivity. Research findings depict the mechanism of ACE2-induced conformational transitions in S trimer structure, aiding in the development of anti-SARS-CoV-2 vaccines and therapeutics.