Human coronavirus HKU1 spike structures reveal the basis for sialoglycan specificity and carbohydrate-promoted conformational changes

Min Jin, Zaky Hassan, Zhijie Li, Ying Liu, Aleksandra Marakhovskaia, Alan H. M. Wong, Adam Forman, Mark Nitz, Michel Gilbert, Hai Yu, Xi Chen and James M. Rini ()
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Min Jin: University of Toronto
Zaky Hassan: University of Toronto
Zhijie Li: University of Toronto
Ying Liu: University of Toronto
Aleksandra Marakhovskaia: University of Toronto
Alan H. M. Wong: University of Toronto
Adam Forman: University of Toronto
Mark Nitz: University of Toronto
Michel Gilbert: National Research Council Canada
Hai Yu: University of California-Davis
Xi Chen: University of California-Davis
James M. Rini: University of Toronto

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract The human coronavirus HKU1 uses both sialoglycoconjugates and the protein transmembrane serine protease 2 (TMPRSS2) as receptors. Carbohydrate binding leads to the spike protein up conformation required for TMPRSS2 binding, an outcome suggesting a distinct mechanism for driving fusion of the viral and host cell membranes. Nevertheless, the conformational changes promoted by carbohydrate binding have not been fully elucidated and the basis for HKU1’s carbohydrate binding specificity remains unknown. Reported here are high resolution cryo-EM structures of the HKU1 spike protein trimer in its apo form and in complex with the carbohydrate moiety of a candidate carbohydrate receptor, the 9-O-acetylated GD3 ganglioside. The structures show that the spike monomer can exist in four discrete conformational states and that progression through them would promote the up conformation upon carbohydrate binding. We also show that a six-amino-acid insert is a determinant of HKU1’s specificity for gangliosides containing a 9-O-acetylated α2–8-linked disialic acid moiety and that HKU1 shows weak affinity for the 9-O-acetylated sialic acids found on decoy receptors such as mucins.

Date: 2025
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DOI: 10.1038/s41467-025-59137-y

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