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

DOI: 10.1371/journal.ppat.1007865 DOI Help

Authors: Roberto Gozalbo-rovira (Centro de Investigación Príncipe Felipe; Facultad de Medicina at Universitat de València) , J. Rafael Ciges-tomas (Instituto de Biomedicina de Valencia (IBV-CSIC); CIBER de Enfermedades Raras (CIBERER)) , Susana Vila-vicent (University of Valencia) , Javier Buesa (University of Valencia) , Cristina Santiso-bellón (University of Valencia) , Vicente Monedero (Institute of Agrochemistry and Food Technology (IATA-CSIC)) , María Jesús Yebra (Institute of Agrochemistry and Food Technology (IATA-CSIC)) , Alberto Marina (Instituto de Biomedicina de Valencia (IBV-CSIC); CIBER de Enfermedades Raras (CIBERER)) , Jesús Rodríguez-díaz (University of Valencia)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Plos Pathogens

State: Published (Approved)
Published: June 2019
Diamond Proposal Number(s): 14739 , 20229

Open Access Open Access

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.

Journal Keywords: Rotavirus infection; Rotavirus; Antigens; Binding analysis; Carbon; Molecular structure; Crystal structure; Crystallization

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: ALBA

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