Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor

Abstract

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 1-3 . 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. 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 . 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. 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 1-3,5 . 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.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 1-3 . 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% 6-8 . 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. As of 5 March 2020, 80,565 cases in China have been confirmed with the infection and 3,015 infected patients have died (https://www.who.int/emergencies/ diseases/novel-coronavirus-2019/situation-reports/). 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.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 . 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. SARS-CoV and other SARSr-CoVs, however, are distinct from SARS-CoV-2 and share less than 80% sequence identity 1 .Coronaviruses use the homotrimeric spike glycoprotein (comprising a S1 subunit and S2 subunit in each spike monomer) on the envelope to ...

Phylogenetic Analysis and Structural Modeling of SARS-CoV-2 Spike Protein Reveals an Evolutionary Distinct and Proteolytically Sensitive Activation Loop

“…Interestingly, we observed in our models that the RBD is predicted to pack similarly to SARS-CoV and the RBM is also predicted to organize as a flexible loop with similar structure despite the lower amino acid identity between these two proteins ( Figure 6). In a more recent report, it has been shown that ACE2-binding mode of both SARS-CoV and SARS-CoV-2 RBDs is nearly identical, which supports the claim that the flexibility in the RBM is key to compensate the amino acid differences between the two CoVs proteins and agrees with our predicted models [54].…”

“…During the preparation of this manuscript, the cryo-electron microscopy structures of SARS-CoV-2 S have recently been determined [33,52,53]. These studies have revealed in detail the structure of the SARS-CoV-2 spike RBD and how it contacts the ACE2 host cell receptor with notable differences compared to SARS-CoV [54]. It has been described that the SARS-CoV RBM "down" conformation packs more closely to the NTD of the S protein [33].…”

Broad Host Range of SARS-CoV-2 Predicted by Comparative and Structural Analysis of ACE2 in Vertebrates

“…The angiotensin I converting enzyme 2 (ACE2) serves as a functional receptor for the spike protein (S) of SARS-CoV and SARS-CoV-2 (12,13) . Under normal physiological conditions, ACE2 is a dipeptidyl carboxypeptidase that catalyzes the conversion of angiotensin I into angiotensin 1-9, a peptide of unknown function, and angiotensin II, a vasoconstrictor that is important in the regulation of blood pressure (14) .…”

“…The host range of SARS-CoV-2 may be extremely broad due to the conservation of ACE2 in mammals (2,13) and its expression on ciliated bronchial epithelial cells and type II pneumocytes (10) . While coronaviruses related to SARS-CoV-2 use ACE2 as a primary receptor, coronaviruses may use other proteases as receptors, such as CD26 (DPP4) for MERS-CoV (16) , thus limiting or extending their host range.…”

A collection of designed peptides to target SARS-Cov-2 – ACE2 interaction: PepI-Covid19 database

“…We use the structure of the SARS-CoV-2 spike receptor-binding domain bound with ACE2 (PDB code 6m0j) 9 and SARS-CoV-2 spike receptor-binding domain bound to full length ACE2 (PDB code 6m17) 4 . The two protein complexes, 6m0j and 6m17, were used in the case of the interface mediating the interaction between the spike protein (S-prot) and ACE2 while the latter was use to model and design peptides to target the interface between ACE2 monomers ( Figure 1).…”