Structural basis of SARS-CoV-2 and its variants binding to intermediate horseshoe bat ACE2

Int J Biol Sci. 2022 Jul 11;18(12):4658-4668. doi: 10.7150/ijbs.73640. eCollection 2022.


Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a global pandemic. Intermediate horseshoe bats (Rhinolophus affinis) are hosts of RaTG13, the second most phylogenetically related viruses to SARS-CoV-2. We report the binding between intermediate horseshoe bat ACE2 (bACE2-Ra) and SARS-CoV-2 receptor-binding domain (RBD), supporting the pseudotyped SARS-CoV-2 viral infection. A 3.3 Å resolution crystal structure of the bACE2-Ra/SARS-CoV-2 RBD complex was determined. The interaction networks of Patch 1 showed differences in R34 and E35 of bACE2-Ra compared to hACE2 and big-eared horseshoe bat ACE2 (bACE2-Rm). The E35K substitution, existing in other species, significantly enhanced the binding affinity owing to its electrostatic attraction with E484 of SARS-CoV-2 RBD. Furthermore, bACE2-Ra showed extensive support for the SARS-CoV-2 variants. These results broaden our knowledge of the ACE2/RBD interaction mechanism and emphasize the importance of continued surveillance of intermediate horseshoe bats to prevent spillover risk.

Keywords: SARS-CoV-2; SARS-CoV-2 variants; bACE2-Ra; intermediate horseshoe bats; structure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2* / genetics
  • Animals
  • Chiroptera*
  • Protein Binding
  • SARS-CoV-2*


  • Angiotensin-Converting Enzyme 2

Supplementary concepts

  • SARS-CoV-2 variants