Crystallography of a Lewis-Binding Norovirus, Elucidation of Strain-Specificity to the Polymorphic Human Histo-Blood Group Antigens

Yutao Chen,Ming Tan,Xuemei Li,Zihe Rao,Pengwei Huang,Ming Xia,Ning Hao,Xi Jiang,Xuejun C Zhang,Barbara Sherry

doi:10.1371/journal.ppat.1002152

Abstract

Noroviruses, an important cause of acute gastroenteritis in humans, recognize the histo-blood group antigens (HBGAs) as host susceptible factors in a strain-specific manner. The crystal structures of the HBGA-binding interfaces of two A/B/H-binding noroviruses, the prototype Norwalk virus (GI.1) and a predominant GII.4 strain (VA387), have been elucidated. In this study we determined the crystal structures of the P domain protein of the first Lewis-binding norovirus (VA207, GII.9) that has a distinct binding property from those of Norwalk virus and VA387. Co-crystallization of the VA207 P dimer with Ley or sialyl Lex tetrasaccharides showed that VA207 interacts with these antigens through a common site found on the VA387 P protein which is highly conserved among most GII noroviruses. However, the HBGA-binding site of VA207 targeted at the Lewis antigens through the α-1, 3 fucose (the Lewis epitope) as major and the β-N-acetyl glucosamine of the precursor as minor interacting sites. This completely differs from the binding mode of VA387 and Norwalk virus that target at the secretor epitopes. Binding pocket of VA207 is formed by seven amino acids, of which five residues build up the core structure that is essential for the basic binding function, while the other two are involved in strain-specificity. Our results elucidate for the first time the genetic and structural basis of strain-specificity by a direct comparison of two genetically related noroviruses in their interaction with different HBGAs. The results provide insight into the complex interaction between the diverse noroviruses and the polymorphic HBGAs and highlight the role of human HBGA as a critical factor in norovirus evolution.

Highlights

Noroviruses, a genus in the family Caliciviridae, are a group of small-round structured, nonenveloped RNA viruses causing epidemic acute gastroenteritis in all age in both developing and developed countries [1,2,3]
The interactions of noroviruses with histo-blood group antigens (HBGAs) are diverse, in which strains in both genogroups I and II (GI and GII) recognizing either the secretor or the non-secretor (Lewis) HBGAs have been reported
VA207 binds to the Lewis antigens via the Lewis epitope (a-1, 3 fucose) as the major interacting residue, which is distinct from the two secretor binders that interact with the secretor antigens through the A or H epitope as a major interacting residue

Summary

Introduction

Noroviruses, a genus in the family Caliciviridae, are a group of small-round structured, nonenveloped RNA viruses causing epidemic acute gastroenteritis in all age in both developing and developed countries [1,2,3]. Norovirus possesses an outer protein capsid that encapsulates a single-stranded, positive sense RNA genome of ,7.5 kb. Norovirus capsid displays an icosahedral symmetry that is composed of 180 copies of a single major structural protein, the capsid protein (VP1), which organize into 90 dimers [4]. Each VP1 can be divided into two major domains, the N-terminal shell (S) and the C-terminal protruding (P) domains, linked by a short hinge. The S domain forms the interior shell; the P domain constitutes the arch-like P dimer of the capsid, while the hinge provides flexibility between the two major domains [4]. The P domain is further divided into P1 and P2 subdomains, forming the leg and the head of the protruding P dimer, respectively [4]

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