Structural Basis for Norovirus Inhibition and Fucose Mimicry by Citrate

Hansman, Grant S.; Shahzad‐ul‐Hussan, Syed; McLellan, Jason S.; Chuang, Gwo-Yu; Georgiev, Ivelin S.; Shimoike, Takashi; Katayama, Kazuhiko; Bewley, Carole A.; Kwong, Peter D.

doi:10.1128/jvi.05909-11

Cited by 77 publications

(65 citation statements)

References 54 publications

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“…2E) (13). A similar group of residues in the P domains of noroviruses was shown to bind glycans (30,31). Alternatively, the putative catalytic site may facilitate the escape of DWV virions from endosomes in a manner analogous to the lipase activity present in the N-terminal domain of the capsid protein VP1 from parvoviruses (32).…”

Section: Resultsmentioning

confidence: 98%

Structure of deformed wing virus, a major honey bee pathogen

Škubník

Nováček

Füzik

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The worldwide population of western honey bees (Apis mellifera) is under pressure from habitat loss, environmental stress, and pathogens, particularly viruses that cause lethal epidemics. Deformed wing virus (DWV) from the family Iflaviridae, together with its vector, the mite Varroa destructor, is likely the major threat to the world's honey bees. However, lack of knowledge of the atomic structures of iflaviruses has hindered the development of effective treatments against them. Here, we present the virion structures of DWV determined to a resolution of 3.1 Åusing cryo-electron microscopy and 3.8 Å by X-ray crystallography. The C-terminal extension of capsid protein VP3 folds into a globular protruding (P) domain, exposed on the virion surface. The P domain contains an Asp-His-Ser catalytic triad that is, together with five residues that are spatially close, conserved among iflaviruses. These residues may participate in receptor binding or provide the protease, lipase, or esterase activity required for entry of the virus into a host cell. Furthermore, nucleotides of the DWV RNA genome interact with VP3 subunits. The capsid protein residues involved in the RNA binding are conserved among honey bee iflaviruses, suggesting a putative role of the genome in stabilizing the virion or facilitating capsid assembly. Identifying the RNA-binding and putative catalytic sites within the DWV virion structure enables future analyses of how DWV and other iflaviruses infect insect cells and also opens up possibilities for the development of antiviral treatments.colony collapse disorder | virus | structure | Apis mellifera | honey bee

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Section: Resultsmentioning

confidence: 98%

Structure of deformed wing virus, a major honey bee pathogen

Škubník

Nováček

Füzik

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Interestingly, we found that citrate can also occupy the HBGA pocket ( Fig. 1) and might perform as a weak natural inhibitor against HBGAs (23,30), comparably to HMOs.…”

Section: Structural Mimicry Of Hbgas and Hmosmentioning

confidence: 88%

“…Moreover, we recently showed that the GII.4 and GII.10 noroviruses actually have four fucose binding pockets per dimer (21,22). The affinity between norovirus and HBGAs is weak and in the high micromolar range (23), and, based on the number of direct hydrogen bonds and water-mediated interactions, small changes in P domain affinities to HBGAs may exist.…”

Section: Structural Basis For Norovirus Binding To Hbgasmentioning

confidence: 99%

Human Norovirus Interactions with Histo-Blood Group Antigens and Human Milk Oligosaccharides

Schroten

Hanisch

Hansman

2016

J Virol

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Human noroviruses interact with both human histo-blood group antigens (HBGAs) and human milk oligosaccharides (HMOs). The former are believed to be important for a virus infection, while the latter might act as natural decoys in the host during an infection. However, certain noroviruses are known to bind poorly to HBGAs and yet still cause infections; some interact with numerous HBGA types but are nonprevalent; and yet others bind HBGAs and seem to be increasing in prevalence. HBGAs and HMOs can be found as soluble antigens in humans, can be structurally alike, and can interact with equivalent residues at identical binding pockets on the capsid. In this Gem, we discuss HBGA and HMO binding studies for human noroviruses, concentrating on the clinically important genogroup II noroviruses. In short, the roles of HBGA and HMO interactions in norovirus infections are still unclear. Human noroviruses are the dominant cause of outbreaks of acute gastroenteritis. These viruses are also responsible for significant numbers of sporadic infections, are often found in asymptomatic cases, can cause chronic infections, and infect all age groups. Noroviruses are transmitted via the fecal-oral route, and infections often result from consumption of contaminated foods such as bivalves (clams and oysters). Noroviruses have a single-stranded, positive-sense RNA genome of ϳ7.5 kb. The genome contains three open reading frames (ORFs): ORF1 encodes nonstructural proteins, ORF2 encodes a capsid protein (VP1), and ORF3 encodes a minor capsid protein. Human norovirus is difficult to grow in cell cultures, and the exact locations of the cells and the cell type(s) that norovirus infect remain unknown. Expression of the capsid protein in insect cells can generate selfassembled virus-like particles (VLPs) that are morphologically and antigenically similar to the native virion (1). The norovirus particle is composed of 180 copies of VP1, which forms 90 VP1 homodimers. The X-ray crystal structure of norovirus VLPs identified two main domains, the shell (S) domain and the protruding (P) domain (2). The S domain surrounds the viral RNA, whereas the P domain is further subdivided into P1 and P2 subdomains and contains determinants for cell attachment and antigenicity. HUMAN NOROVIRUS AND HISTO-BLOOD GROUP ANTIGENSHuman noroviruses are known to interact with histo-blood group antigens (HBGAs), and this interaction could be important for infection (3-7). HBGAs can be found as soluble antigens in saliva and are expressed on the mucosal epithelium of the digestive tract. Therefore, noroviruses could interact several times with HBGAs during the course of an infection. Interestingly, human noroviruses can naturally bioaccumulate in bivalves, where they are thought to bind HBGA-like carbohydrates in the gastrointestinal epithelial cells (8). However, this accumulation does not appear to cause harm to the bivalves.Multiple gene families control human HBGA biosynthesis through the action of glycosyltransferases (9). As HBGAs can be either lipid or protein ...

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“…Lactose showed no inhibition at any concentration, indicating a lack of binding to the VLPs. Our previous results showed that fucose and HBGA H2 trisaccharide had relatively weak (ϳ0.5 mM) affinities to the GII.10 P domain (20). Therefore, considering that 2=FL and 3FL might also have similar affinities and since mothers' milk contains ϳ1 to 5 mM 2=FL/3FL, these HMOs might compete against HBGA binding.…”

Section: Fig 1 Hmos and Blocking Of Binding Of Norovirus Vlps To Hbgamentioning

confidence: 97%

Structural Basis for Norovirus Inhibition by Human Milk Oligosaccharides

Weichert

Koromyslova

Singh

et al. 2016

J Virol

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126

129

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dHisto-blood group antigens (HBGAs) are important binding factors for norovirus infections. We show that two human milk oligosaccharides, 2=-fucosyllactose (2=FL) and 3-fucosyllactose (3FL), could block norovirus from binding to surrogate HBGA samples. We found that 2=FL and 3FL bound at the equivalent HBGA pockets on the norovirus capsid using X-ray crystallography. Our data revealed that 2=FL and 3FL structurally mimic HBGAs. These results suggest that 2=FL and 3FL might act as naturally occurring decoys in humans. Mothers' milk has long been seen as a great source of infant nutrition and protection against a large number of pathogens. Human milk oligosaccharides (HMOs), the third-mostabundant (10 to 15 g/liter) components of human milk, are thought to be in part accountable for these health benefits (1). HMOs are unconjugated complex glycans, and more than 200 isomers are known. HMOs consist of combinations of different monosaccharide building blocks, including fucose, glucose, galactose, N-acetylglucosamine, and the sialic acid derivative N-acetylneuraminic acid. HMOs have been demonstrated to protect against human noroviruses, rotavirus, and certain bacteria (reviewed in reference 2).Human noroviruses are also known to interact with histoblood group antigens (HBGAs), and the interaction is thought to be important for infection (3-6). HBGAs can be found as soluble antigens in saliva and are expressed on epithelial cells. HBGAs consist of monosaccharide building blocks similar to those of HMOs, and at least nine different HBGA types have been found to interact with human norovirus (7-12). HMOs are thought to act as a "receptor decoy" for certain pathogens, since HMOs and HBGAs mimic each other structurally. However, little is known about how HMOs block norovirus infections. One study found that human milk was able to block genogroup I genotype 1 (GI.1) and GII.4 norovirus strains from binding to saliva samples (13). A follow-up study suggested that certain HMOs might compete with the HBGA binding sites on the GI.1 and GII.4 norovirus capsid (14). Despite the fact that human noroviruses are the dominant cause of acute gastroenteritis, there are still no suitable antivirals or vaccines commercially available.In this study, we analyzed the ability of two HMOs, i.e., 2=-fucosyllactose (2=FL) and 3-fucosyllactose (3FL), to block GII.10 norovirus virus-like particles (VLPs) from binding to HBGAs (Fig. 1A). A slightly modified blocking enzyme-linked immunosorbent assay (ELISA) was developed using both porcine gastric mucin type III (PGM) and human saliva (A and B types) (3, 15). The PGM sample was confirmed to contain a mixture of A and H types using specific anti-HBGA monoclonal antibodies (data not shown).The GII.10 VLPs were expressed and purified as previously described (16). The untreated VLPs were first examined for binding to PGM and saliva samples using a direct ELISA. Maxisorp 96-well plates were coated with 100 l per well of 10 g/ml PGM for 4 h at room temperature. The saliva samples were processed in a si...

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Structural Basis for Norovirus Inhibition and Fucose Mimicry by Citrate

Cited by 77 publications

References 54 publications

Structure of deformed wing virus, a major honey bee pathogen

Structure of deformed wing virus, a major honey bee pathogen

Human Norovirus Interactions with Histo-Blood Group Antigens and Human Milk Oligosaccharides

Structural Basis for Norovirus Inhibition by Human Milk Oligosaccharides

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