Receptor-induced activation of MERS-CoV spike revealed by time-course cryo-EM
- 1Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Fifth People’s Hospital, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
Abstract
The Middle East respiratory syndrome coronavirus (MERS-CoV) initiates infection by engaging its host receptor dipeptidyl peptidase 4 (DPP4), which activates the viral spike (S) glycoprotein. However, how receptor binding is structurally coupled to membrane fusion has remained unclear. Here, using cryo–electron microscopy, we determined structures of MERS-CoV spike-DPP4 complexes at defined incubation times, capturing a series of conformational states spanning prefusion, receptor-bound, and postfusion conformations. These structures reveal that receptor-binding domain (RBD) opening progressively weakens S1-S2 interactions, while DPP4 binding may induce conformational drift and loosening of the S2 fusion core. These structural changes might destabilize spike trimers, promote S1 dissociation, and prime the fusion machinery. Compared with the SARS-CoV-2 spike, the MERS-CoV spike exhibits greater conformational plasticity, consistent with a lower threshold for receptor-induced fusion. In addition, the postfusion S2 structure suggests that the HR2 upstream linker may function as a conformational switch during six-helix bundle assembly. Together, these findings outline a structural pathway. for receptor-induced activation of the MERS-CoV spike and provide a structural framework for the development of antiviral strategies targeting dynamic fusion intermediates. Author summary: Middle East respiratory syndrome coronavirus (MERS-CoV) enters host cells using its spike, which binds the cellular receptor DPP4 and subsequently drives membrane fusion. Although this process is essential for viral infection, the structural changes linking receptor binding to membrane fusion have remained poorly understood. In this study, using cryo-electron microscopy, we captured a series of receptor-bound conformational states together with postfusion structures, providing structural snapshots of spike activation. Our results show that receptor binding progressively destabilizes the spike’s fusion machinery and promotes conformational change in a way distinct from SARS-CoV-2, suggesting that different coronaviruses may employ distinct strategies to activate membrane fusion. We also identify a conserved conformational switch that might be important for the final step of membrane fusion, revealing a promising target for pan-coronavirus inhibitor design. Together, these findings improve our understanding of coronavirus entry and provide a structural foundation for developing antiviral agents that target the spike fusion process.
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BibTeX
@article{wang2026receptorinduced,
title = {{Receptor-induced activation of MERS-CoV spike revealed by time-course cryo-EM}},
author = {Yajie Wang and Xiyuan Pan and Yuxuan Jiang and Zhimin Liu and Yinong Qiu and Zhenguo Chen and Lei Sun},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014545},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014545},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Receptor-induced activation of MERS-CoV spike revealed by time-course cryo-EM
AU - Yajie Wang
AU - Xiyuan Pan
AU - Yuxuan Jiang
AU - Zhimin Liu
AU - Yinong Qiu
AU - Zhenguo Chen
AU - Lei Sun
PY - 2026
DA - 2026/10/08
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014545
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014545
AB - The Middle East respiratory syndrome coronavirus (MERS-CoV) initiates infection by engaging its host receptor dipeptidyl peptidase 4 (DPP4), which activates the viral spike (S) glycoprotein. However, how receptor binding is structurally coupled to membrane fusion has remained unclear. Here, using cryo–electron microscopy, we determined structures of MERS-CoV spike-DPP4 complexes at defined incubation times, capturing a series of conformational states spanning prefusion, receptor-bound, and postfusion conformations. These structures reveal that receptor-binding domain (RBD) opening progressively weakens S1-S2 interactions, while DPP4 binding may induce conformational drift and loosening of the S2 fusion core. These structural changes might destabilize spike trimers, promote S1 dissociation, and prime the fusion machinery. Compared with the SARS-CoV-2 spike, the MERS-CoV spike exhibits greater conformational plasticity, consistent with a lower threshold for receptor-induced fusion. In addition, the postfusion S2 structure suggests that the HR2 upstream linker may function as a conformational switch during six-helix bundle assembly. Together, these findings outline a structural pathway. for receptor-induced activation of the MERS-CoV spike and provide a structural framework for the development of antiviral strategies targeting dynamic fusion intermediates. Author summary: Middle East respiratory syndrome coronavirus (MERS-CoV) enters host cells using its spike, which binds the cellular receptor DPP4 and subsequently drives membrane fusion. Although this process is essential for viral infection, the structural changes linking receptor binding to membrane fusion have remained poorly understood. In this study, using cryo-electron microscopy, we captured a series of receptor-bound conformational states together with postfusion structures, providing structural snapshots of spike activation. Our results show that receptor binding progressively destabilizes the spike’s fusion machinery and promotes conformational change in a way distinct from SARS-CoV-2, suggesting that different coronaviruses may employ distinct strategies to activate membrane fusion. We also identify a conserved conformational switch that might be important for the final step of membrane fusion, revealing a promising target for pan-coronavirus inhibitor design. Together, these findings improve our understanding of coronavirus entry and provide a structural foundation for developing antiviral agents that target the spike fusion process.
SN - 1553-7374
ER -