Bat and pangolin coronavirus spike glycoprotein structures provide insights into SARS-CoV-2 evolution

In recognizing the host cellular receptor and mediating fusion of virus and cell membranes, the spike (S) glycoprotein of coronaviruses is the most critical viral protein for cross-species transmission and infection. Here we determined the cryo-EM structures of the spikes from bat (RaTG13) and pangolin (PCoV_GX) coronaviruses, which are closely related to SARS-CoV-2. All three receptor-binding domains (RBDs) of these two spike trimers are in the “down” conformation, indicating they are more prone to adopt the receptor-binding inactive state. However, we found that the PCoV_GX, but not the RaTG13, spike is comparable to the SARS-CoV-2 spike in binding the human ACE2 receptor and supporting pseudovirus cell entry. We further identified critical residues in the RBD underlying different activities of the RaTG13 and PCoV_GX/SARS-CoV-2 spikes. These results collectively indicate that tight RBD–ACE2 binding and efficient RBD conformational sampling are required for the evolution of SARS-CoV-2 to gain highly efficient infection. The spike glycoprotein in coronaviruses is a key viral protein for cross-species transmission and infection. Here, the authors present the cryo-EM structures of the spike ectodomains from bat and pangolin coronaviruses, compare them with the available SARS-CoV-2 spike structures and discuss implications for the evolution and cross-species transmission of SARS-CoV-2.