Coronavirus 229E is the earliest reported human coronavirus (hCoV-229E). Researchers used cryo-EM, glycoproteomics, and modeling to generate the atomic structure of a fully glycosylated and membrane-bound hCoV-229E spike protein bound to its host receptor, human aminopeptidase N (hAPN).
The research was published in Nature Communications.
Human coronavirus 229E (hCoV-229E) was discovered by scientists in 1965 and is the first reported of the seven coronavirus species that infect humans. It recognizes human amino peptidase N (hAPN) as the key to infect humans.
Infection with hCoV-229E can cause respiratory symptoms of a cold, such as headache, runny nose, and sore throat. hCoV-229E infection often occurs simultaneously with respiratory syncytial virus (RSV) infection, which has a greater impact on newborns.
Prof. Shang-Te Danny Hsu's research team at Academia Sinica and National Taiwan University used cryo-electron microscopy (cryo-EM), mass spectrometry (MS), and a recently developed computational tool, known as GlycoSHIELD (published in Cell in 2024 by Prof. Hsu in partnership with European scientists) to analyze how the hCoV-229E surface spike protein recognizes hAPN, as well as the details of post-translational glycosylation modifications of viral and host proteins.
Finally, they established a molecular model of the binding of hCoV-229E spike protein to hAPN. This allowed them to directly see for the first time how hCoV-229E recognizes the hAPN protein in our body through its spike protein to achieve the task of infection, six decades after its discovery.
Through decades of genetic evolution information, Prof. Hsu also found that the hCoV-229E spike protein will increase surface glycosylation modification over time, increasing the shielding effect, which may help immune escape.
The same glycosylation masking phenomenon also occurs in the hemagglutinin protein (HA) of the influenza virus, which makes an important contribution to the design of seasonal influenza vaccines.
"The main research content is based on the thesis of my master student, Ms. Yu-Xi Tsai, at the Institute of Biochemical Sciences at National Taiwan University. Yu-Xi is also the first author of GlycoSHIELD that we published in Cell last year. She will also go to the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany this summer to pursue a doctorate," said Prof. Shang-Te Danny Hsu.
"Thanks to her creative thinking and perseverance, we have finally seen in atomic detail how this oldest human coronavirus recognizes our protein, hAPN, as the target for infection. This work also illustrates how the camouflaging glycan shielding contributes to pathogen-host recognition."
"Our special thanks to the cutting-edge technological support from the Academia Sinica Core Facilities of Cryo-Electron Microscopy, Mass Spectrometry Core Facility, and Biophysics Core Facility, that helped us accomplish this challenging task."
More information: Yu-Xi Tsai et al, Molecular basis of host recognition of human coronavirus 229E, Nature Communications (2025). DOI: 10.1038/s41467-025-57359-8
Journal information: Nature Communications , Cell