Endothelial protein C receptor is an entry receptor for Langya and related parahenipaviruses

Zhao, Z.; Tran, P.; Li, N.; Ou, L.; Song, J.; Sibilo, M.; Castro, M.; Chowdhury, A.; Bohl, J. A.; Wu, J. M.; Do, T. T.; Zhang, B.; Zhao, J.; Pal, A. C.; Mullan, C. W.; Martinez, D. R.; Pierce, R. W.; Spaulding, A.; Lee, S.; Tsybovsky, Y.; Serebryannyy, L.; Douek, D. C.; Zhou, T.; Wilen, C. B.

doi:10.64898/2026.11.01.763137

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bioRxiv · 10.64898/2026.11.01.763137

Endothelial protein C receptor is an entry receptor for Langya and related parahenipaviruses

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Abstract

Langya virus is a zoonotic parahenipavirus with pandemic potential that causes acute febrile illness in people. We identified endothelial protein C receptor (EPCR) as an entry receptor for Langya, Wenzhou, and Mojiang parahenipaviruses. A 3.1 [A] cryo-electron microscopy structure reveals that Langya attachment glycoprotein engages EPCR through a site distinct from that of the ephrin binding site of Nipah G. This binding mode resembles those of protein C and a malarial adhesin, demonstrating convergent evolution. Interface substitutions abolish entry, whereas natural variation explains differential human EPCR use and predicts receptor compatibility across 26 animal species. These findings establish EPCR as a receptor for the Langya clade and provide a structural framework for understanding cross-species transmission and human infection potential.

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Zhao, Z., Tran, P., Li, N., Ou, L., Song, J., Sibilo, M., Castro, M., Chowdhury, A., Bohl, J. A., Wu, J. M., Do, T. T., Zhang, B., Zhao, J., Pal, A. C., Mullan, C. W., Martinez, D. R., Pierce, R. W., Spaulding, A., Lee, S., Tsybovsky, Y., Serebryannyy, L., Douek, D. C., Zhou, T., Wilen, C. B.. 2026-11-02. Endothelial protein C receptor is an entry receptor for Langya and related parahenipaviruses. https://doi.org/10.64898/2026.11.01.763137

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