biostudies-literatureTsai YXAcademia Sinica2045https://www.ebi.ac.uk/biostudies/studies/S-EPMC11868633biostudies-literatureUnknown16(1)Human coronavirus 229E (HCoV-229E) is the earliest CoV found to infect humans. It binds to the human aminopeptidase N (hAPN) through the receptor binding domain (RBD) of its spike (S) protein to achieve host recognition. We present the cryo-electron microscopy structure of two HCoV-229E S protein in complex with a dimeric hAPN to provide structural insights on how the HCoV-229E S protein opens up its RBD to engage with its host receptor, information that is currently missing among alphacoronaviruses to which HCoV-229E belong. We quantitatively profile the glycosylation of HCoV-229E S protein and hAPN to deduce the glyco-shielding effects pertinent to antigenicity and host recognition. Finally, we present an atomic model of fully glycosylated HCoV-229E S in complex with hAPN anchored on theNature communicationsMolecular basis of host recognition of human coronavirus 229E.PMC11868633AS-IV-114-L04AS-IDR-114-S01AS-IDR-111-03AS-IDR-112-04Hsu SDTsai YXChien YCHsu MFKhoo KHfalseMolecular basis of host recognition of human coronavirus 229E.Human coronavirus 229E (HCoV-229E) is the earliest CoV found to infect humans. It binds to the human aminopeptidase N (hAPN) through the receptor binding domain (RBD) of its spike (S) protein to achieve host recognition. We present the cryo-electron microscopy structure of two HCoV-229E S protein in complex with a dimeric hAPN to provide structural insights on how the HCoV-229E S protein opens up its RBD to engage with its host receptor, information that is currently missing among alphacoronaviruses to which HCoV-229E belong. We quantitatively profile the glycosylation of HCoV-229E S protein and hAPN to deduce the glyco-shielding effects pertinent to antigenicity and host recognition. Finally, we present an atomic model of fully glycosylated HCoV-229E S in complex with hAPN anchored on the2025-01-01T00:00:00Z2025 Feb2026-06-02T19:14:19.033Z2025-04-20T01:46:03.112ZS-EPMC118686334001619610.1038/s41467-025-57359-8