Structural comparisons indicated that spike protein utilizes the CTD1 (N-terminal domain in CTD) as the RBD, which changes from the ‘down’ conformation to the ‘up’ conformation and then converts from the inactivated state to the activated state to allow for receptor binding, and possibly also to initiate subsequent conformational changes of the S2 subunits to mediate membrane fusion ( Yuan et al., 2017 Li, 2016 Lan et al., 2020 Kirchdoerfer et al., 2018). The spike protein forms a clove-shaped homotrimer with three S1 heads and a trimeric S2 stalk. Cryo-EM studies have illuminated the prefusion and postfusion structures of the SARS-CoV-1 and SARS-CoV-2 spike proteins, implying that coronaviruses undergo conformational changes during infection. The S2 subunit contains a hydrophobic fusion loop for membrane fusion. The receptor-binding domain (RBD) located in the C-terminal region of the S1 subunit (S1 CTD) is responsible for recognizing and binding the host receptor and is critical in determining the cell tropism, host range, and zoonotic transmission of coronaviruses ( Wu et al., 2020 Li, 2016). After interacting with the host receptor, the spike protein is cleaved into an amino-terminal subunit (S1) and a carboxyl-terminal subunit (S2) by host furin-like proteases ( Yuan et al., 2017 Li, 2016 Lan et al., 2020). The coronavirus spike protein, a class I fusion protein, is synthesized as a precursor single polypeptide chain consisting of three segments: a large ectodomain, a single-pass transmembrane anchor, and a short intracellular tail ( Figure 1A). Envelope-anchored spike proteins are capable of mediating coronavirus entry into host cells by first binding to a specific host receptor and then fusing the viral and host membranes ( Wu et al., 2020 Yuan et al., 2017). SARS-CoV-2, SARS-CoV-1, and MERS-CoV, which infect mammalians ( Wu et al., 2020), are beta-coronaviruses. Considerable efforts have been made to understand its molecule mechanism.Ĭoronaviruses are large, enveloped, positive-stranded RNA viruses belonging to the coronaviridae family, which comprises four genera: alpha-coronaviruses, beta-coronaviruses, gamma-coronaviruses, and delta-coronaviruses ( Zumla et al., 2016). SARS-CoV-2 has caused more than 4 million deaths to date. In late December 2019, a novel coronavirus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the cause of an outbreak of a new respiratory illness named COVID-19. Middle East respiratory syndrome coronavirus (MERS-CoV) has infected over 1700 people with a fatality rate of ~36% since 2012 ( Zaki et al., 2012). In 2003, severe acute respiratory syndrome coronavirus (SARS-CoV-1) emerged in humans after being transferred from an animal reservoir and infected over 8000 people with a fatality rate of ~10% fatality rate ( Ksiazek et al., 2003 Florindo et al., 2020). Over the past 20 years, coronaviruses have posed severe threats to public health. Taken together, these results suggest that the reinforced RBD–ACE2 interaction that results from the N501Y mutation in the RBD should play an essential role in the higher rate of transmission of SARS-CoV-2 variants, and that future mutations in the RBD of the virus should be under surveillance. Molecular dynamics simulations of RBD–ACE2 complexes indicated that the N501Y mutation introduced additional π-π and π-cation interactions that could explain the changes observed by force microscopy. Atomic force microscopy (AFM)-based single-molecule force microscopy (SMFS) consistently quantified the interaction strength of RBD with the mutation as having increased binding probability and requiring increased unbinding force. Remarkably, RBD with the N501Y mutation exhibited a considerably stronger interaction, with a faster association rate and a slower dissociation rate. ![]() To understand the underlying mechanism, we used a cell surface-binding assay, a kinetics study, a single-molecule technique, and a computational method to investigate the interaction between these RBD (mutations) and ACE2. Recently, several variants such as B.1.1.7 (alpha), B.1.351 (beta), and P.1 (gamma), which share a key mutation N501Y on the receptor-binding domain (RBD), appear to be more infectious to humans. SARS-CoV-2 has been spreading around the world for the past year.
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