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A Unique Human Norovirus Lineage with a Distinct HBGA Binding Interface.

Liu W, Chen Y, Jiang X, Xia M, Yang Y, Tan M, Li X, Rao Z - PLoS Pathog. (2015)

Bottom Line: Each of the two major genogroups (GI and GII) of human NoVs recognizes a unique set of HBGAs through a distinct binding interface that is conserved within a genogroup, indicating a distinct evolutionary path for each genogroup.In addition, we found that glycerol inhibits OIF binding to HBGAs, potentially allowing production of cheap antivirals against human NoVs.Taken together, our results reveal a new evolutionary lineage of NoVs selected by HBGAs, a finding that is important for understanding the diversity and widespread nature of NoVs.

View Article: PubMed Central - PubMed

Affiliation: School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.

ABSTRACT
Norovirus (NoV) causes epidemic acute gastroenteritis in humans, whereby histo-blood group antigens (HBGAs) play an important role in host susceptibility. Each of the two major genogroups (GI and GII) of human NoVs recognizes a unique set of HBGAs through a distinct binding interface that is conserved within a genogroup, indicating a distinct evolutionary path for each genogroup. Here, we characterize a Lewis a (Lea) antigen binding strain (OIF virus) in the GII.21 genotype that does not share the conserved GII binding interface, revealing a new evolution lineage with a distinct HBGA binding interface. Sequence alignment showed that the major residues contributing to the new HBGA binding interface are conserved among most members of the GII.21, as well as a closely related GII.13 genotype. In addition, we found that glycerol inhibits OIF binding to HBGAs, potentially allowing production of cheap antivirals against human NoVs. Taken together, our results reveal a new evolutionary lineage of NoVs selected by HBGAs, a finding that is important for understanding the diversity and widespread nature of NoVs.

No MeSH data available.


Related in: MedlinePlus

Identification of the HBGA-binding interface of OIF virus and its interaction with the Lea trisaccharide.(A), (Fo-Fc) omit electron density map of Lea trisaccharide. The omit map was created using the final structure of OIF P domain without Lea trisaccharide, and the mesh map was contoured at 2.0 sigma (blue) around the selection site, with a coverage of 1.6Å radius. Carbon, oxygen and nitrogen atoms are indicated in green, red and blue, respectively. (B), Surface representation of the P dimer of OIF virus in complex with Lea trisaccharide (stick representation). (C and D), Close-ups of top (C) and side (D) views of the HBGA binding interface (surface representations) with indications of the residues that form the HBGA binding interface (colored in green). The Lea trisaccharide (stick representation) is also indicated. The individual saccharides of the Lea-trisaccharide are colored differently: β-Galactose, yellow; α-Fucose, purple; and N-acetyl glucosamine, grey. (E and F), the interacting networks between the side/main chains of the amino acids at the binding interface with the β-Galactose (Gal) and α-Fucose (Fuc) (Le-Fuc). The hydrogen bonds are indicated by dashed lines. The water molecule is presented as a red ball (E) or a circled W (F).
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ppat.1005025.g005: Identification of the HBGA-binding interface of OIF virus and its interaction with the Lea trisaccharide.(A), (Fo-Fc) omit electron density map of Lea trisaccharide. The omit map was created using the final structure of OIF P domain without Lea trisaccharide, and the mesh map was contoured at 2.0 sigma (blue) around the selection site, with a coverage of 1.6Å radius. Carbon, oxygen and nitrogen atoms are indicated in green, red and blue, respectively. (B), Surface representation of the P dimer of OIF virus in complex with Lea trisaccharide (stick representation). (C and D), Close-ups of top (C) and side (D) views of the HBGA binding interface (surface representations) with indications of the residues that form the HBGA binding interface (colored in green). The Lea trisaccharide (stick representation) is also indicated. The individual saccharides of the Lea-trisaccharide are colored differently: β-Galactose, yellow; α-Fucose, purple; and N-acetyl glucosamine, grey. (E and F), the interacting networks between the side/main chains of the amino acids at the binding interface with the β-Galactose (Gal) and α-Fucose (Fuc) (Le-Fuc). The hydrogen bonds are indicated by dashed lines. The water molecule is presented as a red ball (E) or a circled W (F).

Mentions: As shown in previous studies [5, 30], the OIF virus that does not share the conventional GII HBGA binding interface only recognizes Lea antigen. To understand their binding mechanism, we co-crystallized the OIF P domain with Lea trisaccharide (Lea-tri). The P domain-Lea-tri complex was crystallized in P212121 space group, with one homodimer in each asymmetric unit. The Lea-tri is clearly visible in the 2Fo-Fc difference electron density map, with all three rings of the Lea-tri well fitted into the map (Fig 5A). Two symmetric Lea binding interfaces are identified on the top surface of the P dimer (Fig 5B), each of which is formed by eleven residues from the P2 domain of a single protomer. Specifically, residues W296 from the B-loop, S354 and S357 from the N-loop, N392 and T395 from the T-loop form the depressed region at the bottom of the binding pocket (Fig 5C–5E). We noticed that, although S357 does not interact directly with the Lea-tri, it forms a strong hydrogen bond (2.6Å) with the D297 to stabilize the side chain of the latter, ensuring the structural integrity of the binding pocket (Fig 5E and 5F). The surrounding wall of the binding pocket is built by D294 and Y295 from B-loop, T356 and E358 from N-loop, and N394 from T-loop (Fig 5C–5E). None of these residue compositions are conserved with those of the known GII HBGA binding interfaces that is contributed by residues from P-, S-, and A-loops (Figs 2 and 4). The OIF HBGA binding interface also differs completely from those of the GI huNoVs (Fig 4F). Thus, this OIF binding interface represents a previously unrecognized HBGA binding interface.


A Unique Human Norovirus Lineage with a Distinct HBGA Binding Interface.

Liu W, Chen Y, Jiang X, Xia M, Yang Y, Tan M, Li X, Rao Z - PLoS Pathog. (2015)

Identification of the HBGA-binding interface of OIF virus and its interaction with the Lea trisaccharide.(A), (Fo-Fc) omit electron density map of Lea trisaccharide. The omit map was created using the final structure of OIF P domain without Lea trisaccharide, and the mesh map was contoured at 2.0 sigma (blue) around the selection site, with a coverage of 1.6Å radius. Carbon, oxygen and nitrogen atoms are indicated in green, red and blue, respectively. (B), Surface representation of the P dimer of OIF virus in complex with Lea trisaccharide (stick representation). (C and D), Close-ups of top (C) and side (D) views of the HBGA binding interface (surface representations) with indications of the residues that form the HBGA binding interface (colored in green). The Lea trisaccharide (stick representation) is also indicated. The individual saccharides of the Lea-trisaccharide are colored differently: β-Galactose, yellow; α-Fucose, purple; and N-acetyl glucosamine, grey. (E and F), the interacting networks between the side/main chains of the amino acids at the binding interface with the β-Galactose (Gal) and α-Fucose (Fuc) (Le-Fuc). The hydrogen bonds are indicated by dashed lines. The water molecule is presented as a red ball (E) or a circled W (F).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493018&req=5

ppat.1005025.g005: Identification of the HBGA-binding interface of OIF virus and its interaction with the Lea trisaccharide.(A), (Fo-Fc) omit electron density map of Lea trisaccharide. The omit map was created using the final structure of OIF P domain without Lea trisaccharide, and the mesh map was contoured at 2.0 sigma (blue) around the selection site, with a coverage of 1.6Å radius. Carbon, oxygen and nitrogen atoms are indicated in green, red and blue, respectively. (B), Surface representation of the P dimer of OIF virus in complex with Lea trisaccharide (stick representation). (C and D), Close-ups of top (C) and side (D) views of the HBGA binding interface (surface representations) with indications of the residues that form the HBGA binding interface (colored in green). The Lea trisaccharide (stick representation) is also indicated. The individual saccharides of the Lea-trisaccharide are colored differently: β-Galactose, yellow; α-Fucose, purple; and N-acetyl glucosamine, grey. (E and F), the interacting networks between the side/main chains of the amino acids at the binding interface with the β-Galactose (Gal) and α-Fucose (Fuc) (Le-Fuc). The hydrogen bonds are indicated by dashed lines. The water molecule is presented as a red ball (E) or a circled W (F).
Mentions: As shown in previous studies [5, 30], the OIF virus that does not share the conventional GII HBGA binding interface only recognizes Lea antigen. To understand their binding mechanism, we co-crystallized the OIF P domain with Lea trisaccharide (Lea-tri). The P domain-Lea-tri complex was crystallized in P212121 space group, with one homodimer in each asymmetric unit. The Lea-tri is clearly visible in the 2Fo-Fc difference electron density map, with all three rings of the Lea-tri well fitted into the map (Fig 5A). Two symmetric Lea binding interfaces are identified on the top surface of the P dimer (Fig 5B), each of which is formed by eleven residues from the P2 domain of a single protomer. Specifically, residues W296 from the B-loop, S354 and S357 from the N-loop, N392 and T395 from the T-loop form the depressed region at the bottom of the binding pocket (Fig 5C–5E). We noticed that, although S357 does not interact directly with the Lea-tri, it forms a strong hydrogen bond (2.6Å) with the D297 to stabilize the side chain of the latter, ensuring the structural integrity of the binding pocket (Fig 5E and 5F). The surrounding wall of the binding pocket is built by D294 and Y295 from B-loop, T356 and E358 from N-loop, and N394 from T-loop (Fig 5C–5E). None of these residue compositions are conserved with those of the known GII HBGA binding interfaces that is contributed by residues from P-, S-, and A-loops (Figs 2 and 4). The OIF HBGA binding interface also differs completely from those of the GI huNoVs (Fig 4F). Thus, this OIF binding interface represents a previously unrecognized HBGA binding interface.

Bottom Line: Each of the two major genogroups (GI and GII) of human NoVs recognizes a unique set of HBGAs through a distinct binding interface that is conserved within a genogroup, indicating a distinct evolutionary path for each genogroup.In addition, we found that glycerol inhibits OIF binding to HBGAs, potentially allowing production of cheap antivirals against human NoVs.Taken together, our results reveal a new evolutionary lineage of NoVs selected by HBGAs, a finding that is important for understanding the diversity and widespread nature of NoVs.

View Article: PubMed Central - PubMed

Affiliation: School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.

ABSTRACT
Norovirus (NoV) causes epidemic acute gastroenteritis in humans, whereby histo-blood group antigens (HBGAs) play an important role in host susceptibility. Each of the two major genogroups (GI and GII) of human NoVs recognizes a unique set of HBGAs through a distinct binding interface that is conserved within a genogroup, indicating a distinct evolutionary path for each genogroup. Here, we characterize a Lewis a (Lea) antigen binding strain (OIF virus) in the GII.21 genotype that does not share the conserved GII binding interface, revealing a new evolution lineage with a distinct HBGA binding interface. Sequence alignment showed that the major residues contributing to the new HBGA binding interface are conserved among most members of the GII.21, as well as a closely related GII.13 genotype. In addition, we found that glycerol inhibits OIF binding to HBGAs, potentially allowing production of cheap antivirals against human NoVs. Taken together, our results reveal a new evolutionary lineage of NoVs selected by HBGAs, a finding that is important for understanding the diversity and widespread nature of NoVs.

No MeSH data available.


Related in: MedlinePlus