Abstract
Human astrovirus (HAstV) is a major cause of viral enteritis in children and the older adults worldwide. The eight serotypes of classical HAstVs (HAstV1-8), employ the neonatal Fc receptor (FcRn) as an entry receptor. To elucidate the receptor binding mechanism of HAstVs, we determined the crystal structure of the HAstV8 spike protein complexed with human FcRn. The structure reveals that the HAstV8 spike protein engaged FcRn via a conserved surface depression, which is also present across the other seven classical HAstVs serotypes. The binding interface of HAstV8 spike protein on FcRn largely overlaps with the footprints of three clinically approved FcRn blockers to treat an autoimmune disease. Accordingly, these FcRn inhibitors potently suppress astrovirus infection, significantly reducing viral RNA levels in astrovirus permissive Caco2 cells. Therefore, our study reports a conserved receptor recognition mechanism among human astroviruses and suggests the potential of repurposing clinically approved therapeutics to treat astrovirus infection.
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Data availability
Coordinates and structure factors of HAstV8 spike complexed FcRn, HAstV1 spike and HAstV8 spike are available in the Protein Data Bank under accession codes 9WYD, 9WYE and 9WYG, respectively. Source data are provided with this paper.
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Acknowledgements
This work is supported by Scientific Research Innovation Capability Support Project for Young Faculty (Grant No. SRICSPYF-ZY2025124, S.Z.), the Fundamental Research Funds for the Central Universities (Grant Nos. YDZX2026037 and KYQN2022013, Y.X.; KJJQ2025006 and KJJQ2024008, S.Z.), National Natural Science Foundation of China (NSFC, Grant Nos. 32170158, S.Z.; 32100128, Y.X.; 32470138, Y.L.), Jiangsu Agricultural Science and Technology Innovation Fund (CX(23)3074, S.Z.), Natural Science Foundation of Jiangsu Province (Grant Nos. BK20240087, S.Z.; BK20252061 and BK20200553, Y.X.), High-level personnel project of Jiangsu Province (Grant No. JSSCBS20210290, Y.X.). We thank the staff of BL02U1 and BL18U beamlines at Shanghai Synchrotron Radiation Facility for their technical assistance in crystal data collection.
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W.W., Z.L. and K.M. expressed and purified the recombinant proteins. W.W. and D.L. carried out the SPR experiment. W.W. and X.K. grew the virus and performed the ELISA. W.W., Z.L. and R.W. collected the X-ray diffraction data. S.Z. solved the crystal structures. R.C., B.S., X.S., Y.L., X.K., Y.X. and S.Z. designed the experiments. W.W., X.S., Y.L., X.K., Y.X. and S.Z. analyzed the data and wrote the manuscript.
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Wang, W., Xu, Y., Li, Z. et al. The conserved human astrovirus-receptor interface reveals a targetable vulnerability for antiviral development. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70465-5
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DOI: https://doi.org/10.1038/s41467-026-70465-5
