6H9Y

Unraveling the role of the secretor antigen in human rotavirus attachment to histo-blood group antigens

Summary for 6H9Y

• Entry DOI: 10.2210/pdb6h9y/pdb
• Descriptor: Outer capsid protein VP4, beta-D-galactopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (4 entities in total)
• Functional Keywords: histo-blood group antigen rotavirus, viral protein
• Biological source: Human rotavirus A
• Total number of polymer chains: 2
• Total formula weight: 37693.25

Authors

Ciges-Tomas, J.R.,Gozalbo-Rovira, R.,Vila-Vicent, S.,Buesa, J.,Santiso-Bellon, C.,Monedero, V.,Yebra, M.J.,Rodriguez-Diaz, J.,Marina, A. (deposition date: 2018-08-06, release date: 2019-06-12, Last modification date: 2024-01-17)

Primary citation

Gozalbo-Rovira, R.,Ciges-Tomas, J.R.,Vila-Vicent, S.,Buesa, J.,Santiso-Bellon, C.,Monedero, V.,Yebra, M.J.,Marina, A.,Rodriguez-Diaz, J.
Unraveling the role of the secretor antigen in human rotavirus attachment to histo-blood group antigens.
Plos Pathog., 15:e1007865-e1007865, 2019

PubMed Abstract: Rotavirus is the leading agent causing acute gastroenteritis in young children, with the P[8] genotype accounting for more than 80% of infections in humans. The molecular bases for binding of the VP8* domain from P[8] VP4 spike protein to its cellular receptor, the secretory H type-1 antigen (Fuc-α1,2-Gal-β1,3-GlcNAc; H1), and to its precursor lacto-N-biose (Gal-β1,3-GlcNAc; LNB) have been determined. The resolution of P[8] VP8* crystal structures in complex with H1 antigen and LNB and site-directed mutagenesis experiments revealed that both glycans bind to the P[8] VP8* protein through a binding pocket shared with other members of the P[II] genogroup (i.e.: P[4], P[6] and P[19]). Our results show that the L-fucose moiety from H1 only displays indirect contacts with P[8] VP8*. However, the induced conformational changes in the LNB moiety increase the ligand affinity by two-fold, as measured by surface plasmon resonance (SPR), providing a molecular explanation for the different susceptibility to rotavirus infection between secretor and non-secretor individuals. The unexpected interaction of P[8] VP8* with LNB, a building block of type-1 human milk oligosaccharides, resulted in inhibition of rotavirus infection, highlighting the role and possible application of this disaccharide as an antiviral. While key amino acids in the H1/LNB binding pocket were highly conserved in members of the P[II] genogroup, differences were found in ligand affinities among distinct P[8] genetic lineages. The variation in affinities were explained by subtle structural differences induced by amino acid changes in the vicinity of the binding pocket, providing a fine-tuning mechanism for glycan binding in P[8] rotavirus.

PubMed: 31226167
DOI: 10.1371/journal.ppat.1007865

Experimental method

X-RAY DIFFRACTION (1.31 Å)