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Structures and receptor binding activities of merbecovirus spike proteins reveal key signatures for human DPP4

Hang Yuan1,2, Jingjing Wang1, Yong Ma1

  • 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 510530, China.

Science Advances
|July 11, 2025
PubMed

Insights

Merbecoviruses from bats and pangolins use spike proteins to bind human DPP4. Structural analysis reveals conserved binding features and convergent evolution in these zoonotic threats.

Area of Science:

  • Virology
  • Structural Biology
  • Zoonotic Diseases

Background:

  • Merbecoviruses from various animals present zoonotic risks.
  • Understanding spike protein receptor binding is crucial for assessing these threats.

Purpose of the Study:

  • To elucidate the structural basis of merbecovirus spike protein binding to human DPP4.
  • To investigate the evolutionary patterns of merbecovirus receptor utilization.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) to determine structures of viral RBDs and S-trimers.
  • Structure-guided mutagenesis to assess binding affinities.
  • Structure-based phylogenetics to analyze evolutionary relationships.

Main Results:

  • Determined cryo-EM structures of GD-BatCoV and SE-PangolinCoV RBDs with human DPP4.
  • Identified a conserved hydrophobic cluster as a signature for DPP4 binding in MERS-HKU4 clade merbecoviruses.
  • Demonstrated synergistic interactions across RBM regions for high-affinity binding and limited RBM plasticity.
  • Observed convergent evolution in hDPP4-binding merbecoviruses and diversification in ACE2-binding counterparts.

Conclusions:

  • Merbecovirus receptor binding involves complex synergistic interactions and conserved features.
  • Structural insights reveal distinct evolutionary strategies for different receptor-binding merbecoviruses.
  • Findings aid in understanding zoonotic potential and inform future surveillance efforts.

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