![]() However, inspection of one available spike structure revealed the incomplete modelling of the RBD, particularly for the receptor-binding motif (RBM) that interacts directly with ACE2 17. The cryo-electron microscopy structure of the SARS-CoV-2 spike trimer has recently been reported in two independent studies 13, 17. In vitro binding measurements also showed that the SARS-CoV-2 RBD binds to ACE2 with an affinity in the low nanomolar range, indicating that the RBD is a key functional component within the S1 subunit that is responsible for binding of SARS-CoV-2 by ACE2 13, 16. HeLa cells expressing ACE2 are susceptible to SARS-CoV-2 infection whereas those without ACE2 are not 1. Recent studies also highlighted the important role of ACE2 in mediating entry of SARS-CoV-2 1, 13, 14, 15. Therefore, binding to the ACE2 receptor is a critical initial step for SARS-CoV to enter into target cells. Previous cryo-electron microscopy studies of the SARS-CoV spike protein and its interaction with the cell receptor ACE2 have shown that receptor binding induces the dissociation of the S1 with ACE2, prompting the S2 to transit from a metastable pre-fusion to a more-stable post-fusion state that is essential for membrane fusion 9, 10, 11, 12. Such binding triggers a cascade of events that leads to the fusion between cell and viral membranes for cell entry. SARS-CoV and other SARSr-CoVs, however, are distinct from SARS-CoV-2 and share less than 80% sequence identity 1.Ĭoronaviruses use the homotrimeric spike glycoprotein (comprising a S1 subunit and S2 subunit in each spike monomer) on the envelope to bind to their cellular receptors. Bat coronavirus RaTG13 appears to be the closest relative of the SARS-CoV-2, sharing more than 93.1% sequence identity in the spike ( S) gene. Phylogenetic analyses of the coronavirus genomes have revealed that SARS-CoV-2 is a member of the Betacoronavirus genus, which includes SARS-CoV, MERS-CoV, bat SARS-related coronaviruses (SARSr-CoV), as well as others identified in humans and diverse animal species 1, 2, 3, 5. As a result, the epicentre Wuhan and the neighbouring cities have been under lockdown to minimize the continued spread and the WHO (World Health Organization) has announced a Public Health Emergency of International Concern owing to the rapid and global dissemination of SARS-CoV-2. As of 5 March 2020, 80,565 cases in China have been confirmed with the infection and 3,015 infected patients have died ( ). Since the initial outbreak in December of 2019, SARS-CoV-2 has spread throughout China and to more than 80 other countries and areas worldwide. Similar to individuals who were infected by pathogenic SARS-CoV in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, patients infected by SARS-CoV-2 showed a range of symptoms including dry cough, fever, headache, dyspnoea and pneumonia with an estimated mortality rate ranging from 3 to 5% 6, 7, 8. ![]() The emergence of the highly pathogenic coronavirus SARS-CoV-2 in Wuhan and its rapid international spread has posed a serious global public-health emergency 1, 2, 3. The epitopes of two SARS-CoV antibodies that target the RBD are also analysed for binding to the SARS-CoV-2 RBD, providing insights into the future identification of cross-reactive antibodies. Such similarity in structure and sequence strongly indicate convergent evolution between the SARS-CoV-2 and SARS-CoV RBDs for improved binding to ACE2, although SARS-CoV-2 does not cluster within SARS and SARS-related coronaviruses 1, 2, 3, 5. Structural analysis identified residues in the SARS-CoV-2 RBD that are essential for ACE2 binding, the majority of which either are highly conserved or share similar side chain properties with those in the SARS-CoV RBD. The overall ACE2-binding mode of the SARS-CoV-2 RBD is nearly identical to that of the SARS-CoV RBD, which also uses ACE2 as the cell receptor 4. Here, to better understand the initial step of infection at an atomic level, we determined the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 bound to the cell receptor ACE2. A new and highly pathogenic coronavirus (severe acute respiratory syndrome coronavirus-2, SARS-CoV-2) caused an outbreak in Wuhan city, Hubei province, China, starting from December 2019 that quickly spread nationwide and to other countries around the world 1, 2, 3.
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