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Structural basis for sarbecovirus Rc-o319 spike adaptation to Rhinolophus cornutus Bat ACE2 and constraints on
Jingjing Wang1,2, Zexuan Li1,3, Yong Ma1,2
1State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Plos Pathogens
|May 21, 2026
Summary
Bat sarbecoviruses show specific ACE2 binding. Rc-o319 S-protein, with a unique deletion, binds only bat ACE2, limiting cross-species transmission potential due to structural constraints.
Area of Science:
- Virology
- Structural Biology
- Molecular Interactions
Background:
- Bat sarbecoviruses display species-specific Angiotensin-Converting Enzyme 2 (ACE2) binding.
- Understanding receptor specificity is crucial for assessing cross-species transmission risks of sarbecoviruses.
Purpose of the Study:
- To characterize the S-protein of the bat sarbecovirus Rc-o319.
- To investigate the structural and functional basis of its restricted receptor specificity for ACE2.
Main Methods:
- Cryo-electron microscopy (Cryo-EM) to determine S-trimer and complex structures.
- Structure-guided mutagenesis to assess the impact of mutations on ACE2 binding.
- Comparative binding assays to evaluate receptor compatibility.
Main Results:
- Rc-o319 S-protein possesses a unique 9-amino acid deletion in its receptor-binding motif (RBM).
- This deletion results in a novel receptor-binding domain (RBD) with a distinct beta-loop (BL), enabling specific binding to R. cornutus ACE2 (bACE2R.cor) but not human ACE2 (hACE2).
- Simultaneous mutations in the BL and RBM-loop are required for Rc-o319 S-RBD to bind hACE2 with medium-to-high affinity, and bACE2R.cor exhibits limited compatibility with other sarbecoviruses.
Conclusions:
- The Rc-o319 S-protein is a specialized adaptation for binding R. cornutus ACE2.
- Structural constraints, particularly within the BL and RBM-loop, limit the cross-species transmission potential of this sarbecovirus to humans.
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