Crystal structure of the 2019-nCoV spike receptor-binding domain bound with the ACE2 receptor

Abstract

19A novel and highly pathogenic coronavirus (2019-nCoV) has caused an outbreak in Wuhan 20 city, Hubei province of China since December 2019, and soon spread nationwide and spilled 21 over to other countries around the world. To better understand the initial step of infection at 22atomic-level, we determined the crystal structure of the 2019-nCoV spike receptor-binding 23 domain (RBD) bound with the cell receptor ACE2 at 2.45 Å resolution. The overall ACE2-24 binding mode of the 2019-nCoV RBD is nearly identical to that of the SARS-CoV RBD, which 25 also utilizes ACE2 as the cell receptor. Structural analysis identified residues in 2019-nCoV 26 RBD critical for ACE2 binding, and majority of which are either highly conserved or shared 27 similar side chain properties with those in the SARS-CoV RBD. Such similarity in structure 28 and sequence strongly argue for a convergent evolution between 2019-nCoV and SARS-CoV 29 RBD for improved binding to ACE2 despite of being segregated in different genetic lineages 30in the betacoronavirus genus. The epitopes of two SARS-CoV antibodies targeting the RBD 31 are also analyzed with the 2019-nCoV RBD, providing insights into future identification of 32 cross-reactive antibodies.HeLa cells expressing ACE2 is susceptible to 2019-nCoV infection while those without failed 60 to do so 1 . In vitro SPR experiments also showed that the binding affinity of ACE2 to the spike 61 glycoprotein and to the receptor-binding domain (RBD) are equivalent, with the former of 14.7 62 nM and the latter of 15.2 nM 11,12 . These results indicate that the RBD is the key functional 63 component within the S1 subunit responsible for binding to ACE2. 64The cryo-EM structure of the 2019-nCoV spike trimer at 3.5 Å resolution has just been 65 reported 12 . The coordinates are not yet available for detailed characterization. However, 66 inspection of the structure features presented in the uploaded manuscript on bioRxiv indicated 67 author/funder. All rights reserved. No reuse allowed without permission.

COVID-19: Epidemiology, Evolution, and Cross-Disciplinary Perspectives

“…The identification of the contact residues between the receptor-binding domain of S from 2019-nCoV and human ACE2 allows estimation of whether 2019-nCoV could infect other species ( Figure 4A) [72]. To do so, we aligned all available ACE2 amino acid sequences with human ACE2.…”

Spike protein recognition of mammalian ACE2 predicts the host range and an optimized ACE2 for SARS-CoV-2 infection

“…The structure of protein complex between RBD region of S protein of SARS-CoV and human ACE2 has been resolved (PDB: 2AJF) [7]. Recently, the structure of SARS-CoV-2 RBD with human ACE2 was also determined [16,17]. We used Chimera software to display homologous model, and obtained the interaction complex structure of RBD region of SARSr-CoV (SARS-CoV-2 and SARS-CoV) and cat/dog/pangolin/Chinese hamster ACE2.…”

A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV

“…This in vitro neutralization result is consistent with lower affinity binding of CR3022 for SARS-CoV-2, although other explanations are possible as outlined below. SARS-CoV-2 uses the same host receptor, angiotensin I converting enzyme 2 (ACE2) as SARS-CoV (3,(9)(10)(11). Interestingly, the epitope of CR3022 does not overlap with the ACE2binding site (Fig.…”

“…3A). Structural alignment of the CR3022-SARS-CoV-2 RBD complex with the ACE2-SARS-CoV-2 RBD complex (11) further indicates that binding of CR3022 would not clash with ACE2 (12). This analysis implies that the neutralization mechanism of CR3022 for SARS-CoV does not depend on direct blocking of receptor binding, which is consistent with the observation that CR3022 does not compete with ACE2 for binding to the RBD (6).…”