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Structural insights into the receptor-binding domain of bat coronavirus ZXC21

Chenghai Wang1, Xiaoyan Nan1, Yang Deng2

  • 1School of Biomedical Sciences, Hunan University, Changsha, Hunan, China.

Structure (London, England : 1993)
|April 30, 2025
PubMed

Insights

Bat coronaviruses ZXC21 and ZC45 share high genome similarity with SARS-CoV-2 but do not bind human ACE2 receptors. This study reveals the ZXC21 receptor-binding domain structure, offering insights into coronavirus evolution.

Area of Science:

  • Virology
  • Structural Biology
  • Molecular Biology

Background:

  • Bat coronaviruses ZXC21 and ZC45, discovered pre-COVID-19, exhibit significant genome homology (86%) with SARS-CoV-2.
  • Previous research suggests ZXC21 and ZC45 may have played a role in SARS-CoV-2 emergence.
  • The precise cell invasion mechanisms of ZXC21 and ZC45 remain largely uncharacterized.

Purpose of the Study:

  • To elucidate the structural characteristics of the ZXC21 receptor-binding domain (RBD).
  • To investigate the interaction of ZXC21 RBD with known human coronavirus receptors.
  • To assess the potential of SARS-CoV-2-targeting antibodies against ZXC21.

Main Methods:

  • Determined the crystal structure of the ZXC21 receptor-binding domain (RBD).
  • Utilized surface plasmon resonance (SPR) to test interactions between ZXC21 RBD and human coronavirus receptors (ACE2, DPP4, APN, TMPRSS2).
  • Assessed binding of the P5S-3B11 Fab (a SARS-CoV-2 core-targeting antibody) to the ZXC21 RBD.

Main Results:

  • The ZXC21 RBD shares a highly similar core structure with other beta-coronavirus RBDs, including SARS-CoV-2.
  • Distinct receptor-binding motifs (RBMs) were observed in ZXC21 RBD compared to SARS-CoV-2.
  • ZXC21 RBD showed no binding affinity for human ACE2, DPP4, APN, or TMPRSS2.
  • The P5S-3B11 Fab successfully bound to the ZXC21 RBD.

Conclusions:

  • The structural analysis of the ZXC21 RBD provides a basis for understanding its interaction capabilities.
  • ZXC21 does not utilize the primary human coronavirus entry receptors, suggesting different cell invasion pathways.
  • The binding of a SARS-CoV-2 antibody to ZXC21 RBD indicates potential cross-neutralization, warranting further investigation into its therapeutic implications.
  • These findings contribute to understanding the evolutionary landscape of coronaviruses and SARS-CoV-2 origins.
Keywords:
RBDZXC21bat coronaviruscrystal structurehuman beta-coronavirusesneutralizing antibody

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