Structural basis of receptor recognition by SARS-CoV-2

Authors: Shang J et al. Link to paper: https://www.nature.com/articles/s41586-020-2179-y

Journal/ Pre-Print: Nature

Key Words: X-ray crystallography, SARS-COV RBD, SARS-COV-2 RBD, bat SARSr-CoV RaTG13, hACE-2

RESEARCH HIGHLIGHTS 

1. Structural basis for hACE2 recognition by SARS-CoV-2 RBD

2. Higher binding affinity of SARS-CoV-2 RBD, than SARS-CoV RBD, to hACE-2

3. Bat-SARSr-CoV RaTG13 can bind to hACE-2

SUMMARY 

Structural differences were identified between SARS-CoV-2 receptor-binding-domain (RBD) to SARS-CoV RBM, mostly caused by four-residue motif (482-485: GVQG), which allows the hACE2-binding ridge to become more compact and form tighter contact with the N-terminal helix of hACE2 providing a larger binding interface with more contacts than.

Entry of bat RaTG132 pseudovirus was detected into hACE2 expressing cells. The RaTG132 virus shares a similar four-residue motif in the ACE2-binding ridge to SARS-CoV-2, supporting that SARS-CoV-2 might have evolved from the bat SARSr-CoV RaTG132. Residues L486G and Y493Q from RaTG132 to SARS-CoV-2 enhance hACE2 recognition and may facilitate bat-to-human transmission without need for the perceived intermediate Pangolins.

This paper shows functionally important epitopes and neutralizing antibody targets in SARS-CoV-2 RBM to prevent hACE2 binding.

IMPACT FOR SARS-COV2/COVID19 RESEARCH EFFORTS

Understand the virology and/or cell biology of SARS-CoV2/COVID19

Develop a vaccine for SARS-CoV2/COVID19

Treat of SARS-CoV2/COVID19 positive individuals

STUDY TYPE

· In vitro study

STRENGTHS AND LIMITATIONS OF THE PAPER

Novelty: Binding affinity of SARS-CoV-2 RBM to hACE2 compared to SARS-CoV and bat SARSr-CoV RaTG13. Entry of bat SARSr-CoV RaTG13 pseudovirus into hACE2-expressing cells.

Standing in the field: Supportive literature available for RBD binding to hACE-2.

Appropriate statistics: Yes

Viral model used: Pull-down and virus entry experiments were performed with retrovirus pseudotyped spike protein. X-ray crystallography was performed with proteins expressed in insect SF9 cells.

Translatability: Neutralizing antibodies to prevent SARS-CoV-2 RBM binding to hACE2.

Main limitations: The structure is of a chimeric monomer rather than a trimer of the spike protein. They also see a number of occupied N-glycosylation sites and build in the chitobiase core plus the first mannose in all cases, this would be the same in a human cell line as the insect. However even in the insect cell lines this truncated glycan is impossible meaning there would be larger glycans than would have increased stearic effects hence the interaction attributed to the mannose from Asn90 may not occur in vivo.