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Journal of Virology, June 2008, p. 5340-5347, Vol. 82, No. 11
0022-538X/08/$08.00+0     doi:10.1128/JVI.00135-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Structural Basis for the Receptor Binding Specificity of Norwalk Virus{triangledown}

Weiming Bu,1 Aygun Mamedova,1 Ming Tan,2 Ming Xia,2 Xi Jiang,2* and Rashmi S. Hegde1*

Divisions of Developmental Biology,1 Infectious Diseases, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati School of Medicine, 3333 Burnet Avenue, Cincinnati, Ohio 452292

Received 18 January 2008/ Accepted 24 March 2008

Noroviruses are positive-sense, single-stranded RNA viruses that cause acute gastroenteritis. They recognize human histo-blood group antigens as receptors in a strain-specific manner. The structures presented here were analyzed in order to elucidate the structural basis for differences in ligand recognition of noroviruses from different genogroups, the prototypic Norwalk virus (NV; GI-1) and VA387 (GII-4), which recognize the same A antigen but differ in that NV is unable to bind to the B antigen. Two forms of the receptor-binding domain of the norovirus coat protein, the P domain and the P polypeptide, that were previously shown to differ in receptor binding and P-particle formation properties were studied. Comparison of the structures of the NV P domain with and without A trisaccharide and the NV P polypeptide revealed no major ligand-induced changes. The 2.3-Å cocrystal structure reveals that the A trisaccharide binds to the NV P domain through interactions with the residues Ser377, Asp327, His329, and Ser380 in a mode distinct from that previously reported for the VA387 P-domain-A-trisaccharide complex. Mutational analyses confirm the importance of these residues in NV P-particle binding to native A antigen. The {alpha}-GalNAc residue unique to the A trisaccharide is buried deeply in the NV binding pocket, unlike in the structures of A and B trisaccharides bound to VA387 P domain, where the {alpha}-fucose residue forms the most protein contacts. The A-trisaccharide binding mode seen in the NV P domain complex cannot be sterically accommodated in the VA387 P domain.

* Corresponding author. Mailing address for X.J.: Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati School of Medicine, 3333 Burnet Ave., Cincinnati, OH 45229. Phone: (513) 636-0119. Fax: (513) 636-7655. E-mail: jason.jiang{at}cchmc.org. Mailing address for R.S.H.: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati School of Medicine, 3333 Burnet Ave., Cincinnati, OH 45229. Phone: (513) 636-5947. Fax: (513) 636-6772. E-mail: rashmi.hegde{at}cchmc.org

{triangledown} Published ahead of print on 2 April 2008.

Journal of Virology, June 2008, p. 5340-5347, Vol. 82, No. 11
0022-538X/08/$08.00+0     doi:10.1128/JVI.00135-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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