Differences in potential binding interactions were found between ACE2 domain and RBD domain of SARS-CoV-2 and RaTG13 S trimers. SARS-CoV-2 has Phe486 interacting with ACE2 human receptor while the bat virus has Leu486 instead, which is less bulky. SARS-CoV-2 also has a Gln493 that is able to form a hydrogen bond of Glu35 in ACE2, while RaTG13 has a tyrosine that is unlikely to bond with Glu35. More differences are shown in Fig 3b and Fig 3c. These distinctions may impact the differences in S glycoprotein affinity to ACE2 between SARS-CoV-2 and RaTG13. 

Differences in potential binding interactions between ACE2 domain and RBD domain of SARS-CoV-2 and RaTG13 S glycoprotein

"Plot of surface biolayer amplitude measurement as a function of ACE2 concentration with the data for S from SARS-CoV-2 (blue, Kd calculated as 91 ± 18 nM) and from the bat virus (red, Kd estimated to be >40 μM). Kd for the SARS-CoV-2 protein was calculated from kinetic constants (koff = 0.0105 s−1 and kon = 1.56 × 105 m−1 s−1) and was 67.5 ± 9 nM."

Fig 3a. Binding of ACE2 receptor to bat virus and SARS-CoV-2 S proteins

Amplitude analysis provides evidence that SARS-CoV-2 binds more tightly to human ACE2 than the bat virus protein does by around 1,000 times. 

University of Michigan - Ann Arbor

- Cry-electron microscopy (cryo-EM) structures of S glycoprotein of bat virus RaTG13 and uncleaved SARS-CoV-2
- S glycoprotein sequences of RaTG13 and SARS-CoV-2
- S glycoprotein stability 
- Bat virus RaTG13 and SARS-CoV-2 S glycoprotein affinities to human receptor ACE2

Comparison of S glycoprotein between RaTG13 and uncleaved SARS-CoV-2

Wrobel, A.G., Benton, D.J., Xu, P. et al. SARS-CoV-2 and bat RaTG13 spike glycoprotein structures inform on virus evolution and furin-cleavage effects. Nat Struct Mol Biol (2020). https://doi.org/10.1038/s41594-020-0468-7

SARS-CoV-2 and bat RaTG13 spike glycoprotein structures inform on virus evolution and furin-cleavage effects

Cry-electron microscopy (cryo-EM) structures of S glycoprotein of bat virus RaTG13 and an uncleaved SARS-CoV-2 were created. The structure of the S glycoprotein in RaTG13 is shown to be very similar to that of the closed form of uncleaved SARS-CoV-2.

Cry-electron microscopy (cryo-EM) structures of S glycoprotein of bat virus RaTG13 and uncleaved SARS-CoV-2

The S protein sequences of both the RaTG13 and SARS-CoV-2 were 97.8% conservative in the ectodomain. However, 89.6% of the sequence in the receptor-binding domain (RBD) varied, with substitutions in the ACE2-receptor-binding surface and the RBD–RBD interfaces of the trimeric S.

S glycoprotein sequences of RaTG13 and SARS-CoV-2

Using thermal-stability data, it was concluded that the uncleaved SARS-CoV-2 S protein had higher stability than RaTG13 S protein and cleaved SARS-CoV-2 had similar stability to uncleaved RaTG13 protein. 

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