title: Elucidation of strain-specific interaction of a GII-4 norovirus with HBGA receptors by site-directed mutagenesis study.
abstract: Noroviruses interact with histo-blood group antigen (HBGA) receptors in a strain-specific manner probably detecting subtle structural differences in the carbohydrate receptors. The specific recognition of types A and B antigens by various norovirus strains is a typical example. The only difference between the types A and B antigens is the acetamide linked to the terminal galactose of the A but not to the B antigen. The crystal structure of the P dimer of a GII-4 norovirus (VA387) bound to types A and B trisaccharides has elucidated the A/B binding site on the capsid but did not explain the binding specificity of the two antigens. In this study, using site-directed mutagenesis, we have identified three residues on the VA387 capsid that are sterically close to the acetamide and are required for binding to A but not B antigens, indicating that the acetamide determines the binding specificity between the A and B antigens. Further mutational analysis showed that a nearby open cavity may also be involved in binding specificity to HBGAs. In addition, a systematic mutational analysis of residues in and around the binding interface has identified a group of amino acids that are required for binding but do not have direct contact with the carbohydrate antigens, implying that these residues may be involved in the structural integrity of the receptor binding interface. Taken together, our study provides new insights into the carbohydrate/capsid interactions which are a valuable complement to the atomic structures in understanding the virus/host interaction and in the future design of antiviral agents.
authors.affiliation: Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Tan
authors.forename: Ming
authors.initials: M
authors.lastname: Xia
authors.forename: Sheng
authors.initials: S
authors.lastname: Cao
authors.forename: Pengwei
authors.initials: P
authors.lastname: Huang
authors.forename: Tibor
authors.initials: T
authors.lastname: Farkas
authors.forename: Jarek
authors.initials: J
authors.lastname: Meller
authors.forename: Rashmi S
authors.initials: RS
authors.lastname: Hegde
authors.forename: Xuemei
authors.initials: X
authors.lastname: Li
authors.forename: Zihe
authors.initials: Z
authors.lastname: Rao
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
mesh_terms: D000017:ABO Blood-Group System / Q000737:chemistry / Q000378:metabolism*; D000081:Acetamides / Q000737:chemistry; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D036022:Capsid Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002236:Carbohydrate Conformation; D017124:Conserved Sequence; D017931:DNA Primers / Q000235:genetics; D019281:Dimerization; D005690:Galactose / Q000737:chemistry; D054884:Host-Pathogen Interactions; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D029322:Norovirus / Q000145:classification / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology*; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D017386:Sequence Homology, Amino Acid
chemical_list: D000017:ABO Blood-Group System; D000081:Acetamides; D036022:Capsid Proteins; D017931:DNA Primers; D005690:Galactose