Abstract
SARS-CoV-2 is thought to have emerged from bats, possibly via a secondary host. Here, we investigate the relationship of spike (S) glycoprotein from SARS-CoV-2 with the S protein of a closely related bat virus, RaTG13. We determined cryo-EM structures for RaTG13 S and for both furin-cleaved and uncleaved SARS-CoV-2 S; we compared these with recently reported structures for uncleaved SARS-CoV-2 S. We also biochemically characterized their relative stabilities and affinities for the SARS-CoV-2 receptor ACE2. Although the overall structures of human and bat virus S proteins are similar, there are key differences in their properties, including a more stable precleavage form of human S and about 1,000-fold tighter binding of SARS-CoV-2 to human receptor. These observations suggest that cleavage at the furin-cleavage site decreases the overall stability of SARS-CoV-2 S and facilitates the adoption of the open conformation that is required for S to bind to the ACE2 receptor.
Highlights
SARS-CoV-2 is thought to have emerged from bats, possibly via a secondary host
The surface of the receptor-binding domain (RBD), which would interact with the angiotensin-converting enzyme 2 (ACE2) receptor, is buried inside the trimer and is not accessible for receptor binding
The third RBD rotates ~60 ̊ such that the ACE2-interacting surface becomes fully exposed at the top of the assembly, whereas the NTD of the adjacent chain moves toward the rotated domain, with the NTD of the same chain moving
Summary
SARS-CoV-2 is thought to have emerged from bats, possibly via a secondary host. Here, we investigate the relationship of spike (S) glycoprotein from SARS-CoV-2 with the S protein of a closely related bat virus, RaTG13. The overall structures of human and bat virus S proteins are similar, there are key differences in their properties, including a more stable precleavage form of human S and about 1,000-fold tighter binding of SARS-CoV-2 to human receptor These observations suggest that cleavage at the furin-cleavage site decreases the overall stability of SARS-CoV-2 S and facilitates the adoption of the open conformation that is required for S to bind to the ACE2 receptor. In order to examine the evolutionary origin of SARS-CoV-2 and to better understand the emergence of the COVID-19 pandemic, here we have characterized the S proteins of SARS-CoV-2 and RaTG13, determined their affinities for human ACE2 and investigated the effects of furin cleavage on the structure of S from SARS-CoV-2
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