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Abstract The prototypic henipaviruses (HNV), Hendra (HeV) and Nipah (NiV), are emergent zoonotic pathogens responsible for frequent and fatal outbreaks of severe disease in domestic animals and humans. The HNV attachment glycoprotein (G) is a critical determinant of host-species and cell-type tropism. Utilization of highly conserved B-type ephrin ligands as functional entry receptors engenders HNVs with a broad permissive host range, accounts for zoonotic spillover, and is closely aligned with observed disease pathologies. Recent studies have uncovered numerous divergent clades of HNVs globally. Cedar virus (CedV), the closest relative of HeV and NiV identified to date, can establish experimental infections, yet has not been observed to cause overt disease. While the apathogenic phenotype may be attributed to a lack of P-gene derived interferon antagonists, the V and W accessory proteins, additional determinants of differential HNV pathobiology could be involved. Here, through comparative functional and structural analysis of CedV-G, we characterize molecular interactions critical to viral entry. We demonstrate that CedV possesses a unique cellular entry receptor repertoire which, in addition to functional utilization of the common HNV receptor, ephrin-B2, includes the hitherto uncharacterized interaction with ephrin-B1. Crystal structures reveal a conserved recognition mode between diverse HNV-G proteins and their distinct ephrin receptors and identify a region of molecular specificity within CedV-G that is a key determinant of ephrin selectivity. This work provides a platform for understanding the functional diversity and varied receptor tropism characteristics of HNV glycoproteins that will facilitate assessment of the pathogenic potential and transmissibility of newly discovered and uncharacterized HNVs.

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