Structural basis of receptor recognition by SARS-CoV-2
Shang, J., Ye, G., Shi, K. et al. Structural basis of receptor recognition by SARS-CoV-2. Nature 581, 221–224 (2020). https://doi.org/10.1038/s41586-020-2179-y
Review written by:
Daniel D Roybal, edited by Rinki Saha
Green - In-depth comparison between coronaviruses keeping the main focus on the molecular interactions, essential for the virus/receptor binding. The well-written discussion section details convincing hypotheses on how the virus was transmitted from bat to humans via intermediate host pangolins. The use of a chimeric protein to obtain a stable structure is innovative but may invite criticisms on dissimilarity to the unaltered wild-type SARS-CoV-2 RBD.
The goal of this study was to generate a crystal structure of SARS-CoV-2 bound to hACE2 and study molecular interactions between the two units. The receptor binding domain (RBD) on the coronavirus spike protein mediates the interaction between the virus and the receptor. The RBD consists of a core and a receptor binding motif (RBM). In order to take advantage of this crystallized complex, a chimeric protein was generated that consists of the RBD core from SARS-CoV and the RBM from SARS-CoV. The addition of a short loop from SARS-CoV RBM that forms a strong salt bridge with hACE2 was critical in obtaining crystallization under the same conditions previously used for SARS-CoV RBD/ hACE2.
A Surface plasmon resonance assay was utilized to determine the hACE2-binding affinity of the generated chimera. A glycan-interacting arginine that assists in binding is conserved between SARS-CoV and SARS-CoV-2. Furthermore, SARS-CoV and SARS-CoV-2 RBMs have a binding ridge that binds to the exposed surface of hACE2. The ridge is distinct between SARS-CoV and bat coronavirus Rs3367 versus that in SARS-CoV-2 and bat coronavirus RaTG13, resulting in different conformation of the ridge which allows for higher binding affinity between this virus and hACE2. Additionally, Phe486 on SARS-CoV-2 inserts into a hydrophobic pocket on hACE2 allowing a favorable recognition and binding.
Two virus-binding hotspots at the interface between the RBM of SARS-CoV and hACE2 are structurally altered at the binding interface of SARS-CoV-2 and hACE2. Mutations at these hotspot residues in SARS-CoV-2 reduced binding affinity of the virus to hACE2. Additionally, introduced mutations at the binding ridge of SARS-CoV-2 critically reduced binding affinity. Finally, the authors determined that hACE2 is the binding receptor for bat coronavirus RaTG13 using a pseudovirus entry assay. The binding ridge and other binding-favorable amino acids on RaTG13 were similar to those in SARS-CoV-2.