scholarly journals Human Group C Rotavirus VP8*s Recognize Type A Histo-Blood Group Antigens as Ligands

2018 ◽  
Vol 92 (11) ◽  
Author(s):  
Xiaoman Sun ◽  
Lihong Wang ◽  
Jianxun Qi ◽  
Dandi Li ◽  
Mengxuan Wang ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
Blood Group ◽  
Specific Interaction ◽  
Type A ◽  
Host Susceptibility ◽  
Structural Basis ◽  
Receptor Interaction ◽  
Blood Group Antigens ◽  
Group Species

ABSTRACTGroup/species C rotaviruses (RVCs) have been identified as important pathogens of acute gastroenteritis (AGE) in children, family-based outbreaks, as well as animal infections. However, little is known regarding their host-specific interaction, infection, and pathogenesis. In this study, we performed serial studies to characterize the function and structural features of a human G4P[2] RVC VP8* that is responsible for the host receptor interaction. Glycan microarrays demonstrated that the human RVC VP8* recognizes type A histo-blood group antigens (HBGAs), which was confirmed by synthetic glycan-/saliva-based binding assays and hemagglutination of red blood cells, establishing a paradigm of RVC VP8*-glycan interactions. Furthermore, the high-resolution crystal structure of the human RVC VP8* was solved, showing a typical galectin-like structure consisting of two β-sheets but with significant differences from cogent proteins of group A rotaviruses (RVAs). The VP8* in complex with a type A trisaccharide displays a novel ligand binding site that consists of a particular set of amino acid residues of the C-D, G-H, and K-L loops. RVC VP8* interacts with type A HBGAs through a unique mechanism compared with that used by RVAs. Our findings shed light on the host-virus interaction and the coevolution of RVCs and will facilitate the development of specific antivirals and vaccines.IMPORTANCEGroup/species C rotaviruses (RVCs), members ofReoviridaefamily, infect both humans and animals, but our knowledge about the host factors that control host susceptibility and specificity is rudimentary. In this work, we characterized the glycan binding specificity and structural basis of a human RVC that recognizes type A HBGAs. We found that human RVC VP8*, the rotavirus host ligand binding domain that shares only ∼15% homology with the VP8* domains of RVAs, recognizes type A HBGA at an as-yet-unknown glycan binding site through a mechanism distinct from that used by RVAs. Our new advancements provide insights into RVC-cell attachment, the critical step of virus infection, which will in turn help the development of control and prevention strategies against RVs.

scholarly journals GII.13/21 Noroviruses Recognize Glycans with a Terminal β-Galactose via an Unconventional Glycan Binding Site

2019 ◽  
Vol 93 (15) ◽  
Author(s):  
Xin Cong ◽  
Xiao-man Sun ◽  
Jian-xun Qi ◽  
Han-bo Li ◽  
Wen-gang Chai ◽  
...  
Keyword(s):  
Binding Site ◽  
Blood Group ◽  
Binding Mode ◽  
Host Susceptibility ◽  
Genetic Lineage ◽  
Blood Group Antigens ◽  
Human Noroviruses ◽  
Control And Prevention ◽  
P Domain ◽  
Glycan Receptors

ABSTRACT Human noroviruses (huNoVs) recognize histo-blood group antigens (HBGAs) as host susceptibility factors. GII.13 and GII.21 huNoVs form a unique genetic lineage that emerged from mainstream GII NoVs via development of a new, nonconventional glycan binding site (GBS) that binds Lea antigen. This previous finding raised the question of whether the new GII.13/21 GBS really has such a narrow glycan binding spectrum. In this study, we provide solid phenotypic and structural evidence indicating that this new GBS recognizes a group of glycans with a common terminal β-galactose (β-Gal). First, we found that P domain proteins of GII.13/21 huNoVs circulating at different times bound three glycans sharing a common terminal β-Gal, including Lec, lactose, and mucin core 2. Second, we solved the crystal structures of the GII.13 P dimers in complex with Lec and mucin core 2, which showed that β-Gal is the major binding saccharide. Third, nonfat milk and lactose blocked the GII.13/21 P domain-glycan binding, which may explain the low prevalence of GII.13/21 viruses. Our data provide new insight into the host interactions and epidemiology of huNoVs, which would help in the control and prevention of NoV-associated diseases. IMPORTANCE Evidence from both phenotypic binding assay and structural study support the observed interactions of human noroviruses (huNoVs) with histo-blood group antigens (HBGAs) as receptors or attachment factors, affecting their host susceptibility. GII.13 and GII.21 genotypes form a unique genetic lineage that differs from the mainstream GII huNoVs in their unconventional glycan binding site. Unlike the previous findings that GII.13/21 genotypes recognize only Lea antigen, we found in this study that they can interact with a group of glycans with a common terminal β-Gal, including Lec, lactose, and mucin core 2. However, this wide glycan binding spectrum in a unique binding mode of the GII.13/21 huNoVs appears not to increase their prevalence, probably due to the existence of decoy glycan receptors in human gastrointestinal tract limiting their infection. Our findings shed light on the host interaction and epidemiology of huNoVs, which would impact the strategy of huNoV control and prevention.

scholarly journals Minimizing the Entropy Penalty for Ligand Binding: Lessons from the Molecular Recognition of the Histo Blood‐Group Antigens by Human Galectin‐3

2019 ◽  
Vol 131 (22) ◽  
pp. 7346-7350 ◽  
Author(s):  
Ana Gimeno ◽  
Sandra Delgado ◽  
Pablo Valverde ◽  
Sara Bertuzzi ◽  
Manuel Alvaro Berbís ◽  
...  
Keyword(s):  
Molecular Recognition ◽  
Ligand Binding ◽  
Blood Group ◽  
Blood Group Antigens ◽  
Galectin 3

scholarly journals A structural basis for how ligand binding site changes can allosterically regulate GPCR signaling and engender functional selectivity

2020 ◽  
Vol 13 (617) ◽  
pp. eaaw5885 ◽  
Author(s):  
Marta Sanchez-Soto ◽  
Ravi Kumar Verma ◽  
Blair K. A. Willette ◽  
Elizabeth C. Gonye ◽  
Annah M. Moore ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
G Protein ◽  
Structural Basis ◽  
Protein Signaling ◽  
Ligand Binding Site ◽  
Intracellular Loop ◽  
Gpcr Signaling ◽  
Biased Signaling ◽  
Dynamics Simulations

Signaling bias is the propensity for some agonists to preferentially stimulate G protein–coupled receptor (GPCR) signaling through one intracellular pathway versus another. We previously identified a G protein–biased agonist of the D2 dopamine receptor (D2R) that results in impaired β-arrestin recruitment. This signaling bias was predicted to arise from unique interactions of the ligand with a hydrophobic pocket at the interface of the second extracellular loop and fifth transmembrane segment of the D2R. Here, we showed that residue Phe189 within this pocket (position 5.38 using Ballesteros-Weinstein numbering) functions as a microswitch for regulating receptor interactions with β-arrestin. This residue is relatively conserved among class A GPCRs, and analogous mutations within other GPCRs similarly impaired β-arrestin recruitment while maintaining G protein signaling. To investigate the mechanism of this signaling bias, we used an active-state structure of the β2-adrenergic receptor (β2R) to build β2R-WT and β2R-Y1995.38A models in complex with the full β2R agonist BI-167107 for molecular dynamics simulations. These analyses identified conformational rearrangements in β2R-Y1995.38A that propagated from the extracellular ligand binding site to the intracellular surface, resulting in a modified orientation of the second intracellular loop in β2R-Y1995.38A, which is predicted to affect its interactions with β-arrestin. Our findings provide a structural basis for how ligand binding site alterations can allosterically affect GPCR-transducer interactions and result in biased signaling.

scholarly journals Non-secretion of ABO blood group antigens as a host susceptibility factor in the spondyloarthropathies.

BMJ ◽  
1987 ◽  
Vol 294 (6566) ◽  
pp. 208-210 ◽  
Author(s):  
R Shinebaum ◽  
C C Blackwell ◽  
P J Forster ◽  
N P Hurst ◽  
D M Weir ◽  
...  
Keyword(s):  
Blood Group ◽  
Host Susceptibility ◽  
Abo Blood Group ◽  
Blood Group Antigens ◽  
Susceptibility Factor

scholarly journals Histochemical reactivity of the Geodia cydonium agglutinin (GCA) in human tissues.

1991 ◽  
Vol 39 (4) ◽  
pp. 491-505 ◽  
Author(s):  
M Vierbuchen ◽  
G Uhlenbruck ◽  
F G Hanisch ◽  
W E Müller ◽  
M Ortmann ◽  
...  
Keyword(s):  
Binding Site ◽  
Blood Group ◽  
Lectin Binding ◽  
Blood Group Antigens ◽  
Group Status ◽  
Geodia Cydonium ◽  
Group A ◽  
Complex Carbohydrates ◽  
Group B ◽  
Inhibition Studies

We applied a peroxidase-antiperoxidase technique to study the distribution pattern and binding characteristics of the lectin from the marine sponge Geodia cydonium (Geodia cydonium agglutinin; GCA) in various human tissues. This lectin has been shown to possess a broad reactivity, but there was a distinct distribution of binding sites within the different organs. In the histochemical system GCA displayed no blood group specificity and labeled red blood cells, the vascular endothelium, and epithelial cells showing blood group antigen expression independent of the ABH blood group status. However, inhibition of GCA reactivity by simple sugars and complex carbohydrates demonstrated tissue-specific differences of lectin binding related to the ABH blood group status of the tissue and revealed information on the structural requirements of the histological lectin binding site. Tissues that totally lacked blood group antigens or that expressed only the H-antigen disclosed a GCA reactivity which was completely inhibited by lactose. In contrast, tissues that expressed blood group A- or blood group B-antigen exhibited a lactose-resistant lectin binding which was inhibited only by water-soluble blood group substance A from peptone A and by bovine glycophorin but not by other complex carbohydrates, including human glycophorin and human asialoglycophorin. Competitive inhibition studies in situ revealed that GCA binding was not inhibited by blood group type I/II carbohydrate sequence-specific lectins or by lectins with other sugar specificities. Inhibition by lactose of GCA binding to some histological sites indicates that the binding site consists of a beta-linked galactose-containing disaccharide. However, periodate oxidation of tissue sections had no effect on lectin binding, pointing to a subterminal location of the relevant sequence. The results obtained from inhibition studies with simple saccharides and complex carbohydrates in relation to the expression of ABH blood group antigens suggest a complex lectin combining site(s) in histological specimens. The lectin may possess either one binding site with a range of affinities for different carbohydrates (besides beta-linked disaccharides the GCA binding site accommodates to carbohydrate determinants carrying the blood group A or blood group B determinant), or may possess two different binding sites. Besides an acceptor site for beta-linked disaccharides, an additional binding site may exist accommodating to extended carbohydrate sequences related to A or B blood group structures. In conclusion, GCA represents a blood group-nonspecific lectin whose binding affinities are determined by the ABH blood group status of the tissue.

scholarly journals Norovirus and Histo-Blood Group Antigens: Demonstration of a Wide Spectrum of Strain Specificities and Classification of Two Major Binding Groups among Multiple Binding Patterns

2005 ◽  
Vol 79 (11) ◽  
pp. 6714-6722 ◽  
Author(s):  
Pengwei Huang ◽  
Tibor Farkas ◽  
Weiming Zhong ◽  
Ming Tan ◽  
Scott Thornton ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Blood Group ◽  
Acute Gastroenteritis ◽  
Specific Binding ◽  
Wide Spectrum ◽  
Phylogenetic Analyses ◽  
Lewis Antigens ◽  
Blood Group Antigens ◽  
Multiple Binding

ABSTRACT Noroviruses, an important cause of acute gastroenteritis, have been found to recognize human histo-blood group antigens (HBGAs) as receptors. Four strain-specific binding patterns to HBGAs have been described in our previous report. In this study, we have extended the binding patterns to seven based on 14 noroviruses examined. The oligosaccharide-based assays revealed additional epitopes that were not detected by the saliva-based assays. The seven patterns have been classified into two groups according to their interactions with three major epitopes (A/B, H, and Lewis) of human HBGAs: the A/B-binding group and the Lewis-binding group. Strains in the A/B binding group recognize the A and/or B and H antigens, but not the Lewis antigens, while strains in the Lewis-binding group react only to the Lewis and/or H antigens. This classification also resulted in a model of the norovirus/HBGA interaction. Phylogenetic analyses showed that strains with identical or closely related binding patterns tend to be clustered, but strains in both binding group can be found in both genogroups I and II. Our results suggest that noroviruses have a wide spectrum of host range and that human HBGAs play an important role in norovirus evolution. The high polymorphism of the human HBGA system, the involvement of multiple epitopes, and the typical protein/carbohydrate interaction between norovirus VLPs and HBGAs provide an explanation for the virus-ligand binding diversities.

scholarly journals N-glycolylneuraminic acid and N-acetylneuraminic acid define feline blood group A and B antigens

Blood ◽  
1992 ◽  
Vol 79 (9) ◽  
pp. 2485-2491 ◽  
Author(s):  
GA Andrews ◽  
PS Chavey ◽  
JE Smith ◽  
L Rich
Keyword(s):  
Membrane Protein ◽  
Blood Group ◽  
Type A ◽  
Blood Type ◽  
Blood Group Antigens ◽  
Type B ◽  
Western Blots ◽  
Acetylneuraminic Acid ◽  
Group A ◽  
Type Ab

Abstract Blood group incompatibility causes transfusion reactions and neonatal isoerythrolysis in cats. We investigated the molecular nature of the blood group antigens from cats that had blood type A, B, and AB erythrocytes. Naturally occurring anti-type B antibodies, Triticum vulgaris lectin, monoclonal antibody (MoAb) 32–27, and MoAb R-24 were used in agglutination tests, Western blots, and thin-layer chromatography (TLC) enzyme immunostaining. Type A erythrocytes had NeuGc-NeuGc-Galactose-Glucose-Ceramide ([NeuGc]2GD3) where NeuGc represents N-glycolylneuraminic acid, and NeuAc-NeuGc-GD3, where NeuAc represents N-acetylneuraminic acid, and may have [NeuGc]2 disialylparagloboside and NeuAc-NeuGc-disialylparagloboside. Type B erythrocytes only had [NeuAc]2GD3. Type AB erythrocytes had [NeuGc]2GD3, NeuAc-NeuGc-GD3, and [NeuAc]2GD3. Blood group antigens were also found on a 50-Kd membrane protein. We conclude that type B erythrocytes are characterized by [NeuAc]2GD3 as the only form of this ganglioside and the presence of NeuAc on a 50-Kd membrane protein. NeuGc is the major determinant of the A antigen; specifically, [NeuGc]2GD3 is the major glycolipid form. The A antigen is also present on a 50-Kd membrane protein.

scholarly journals Structural Basis for Norovirus Inhibition by Human Milk Oligosaccharides

2016 ◽  
Vol 90 (9) ◽  
pp. 4843-4848 ◽  
Author(s):  
Stefan Weichert ◽  
Anna Koromyslova ◽  
Bishal K. Singh ◽  
Satoko Hansman ◽  
Stefan Jennewein ◽  
...  
Keyword(s):  
Human Milk ◽  
Blood Group ◽  
Structural Basis ◽  
Blood Group Antigens ◽  
Human Milk Oligosaccharides ◽  
Milk Oligosaccharides ◽  
X Ray ◽  
X Ray Crystallography ◽  
Naturally Occurring

Histo-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.

Critical residues for ligand binding in blade 2 of the propeller domain of the integrin αIIb subunit

2004 ◽  
Vol 91 (01) ◽  
pp. 111-118 ◽  
Author(s):  
Tatsushiro Tamura ◽  
Jun Yamanouchi ◽  
Shigeru Fujita ◽  
Takaaki Hato
Keyword(s):  
Crystal Structure ◽  
Ligand Binding ◽  
Binding Site ◽  
Thrombus Formation ◽  
Direct Interaction ◽  
Binding Pocket ◽  
Crystal Structure Analysis ◽  
Site Directed Mutagenesis ◽  
Structural Basis ◽  
Critical Residues

SummaryLigand binding to integrin αIIbβ3 is a key event of thrombus formation. The propeller domain of the αIIb subunit has been implicated in ligand binding. Recently, the ligand binding site of the αV propeller was determined by crystal structure analysis. However, the structural basis of ligand recognition by the αIIb propeller remains to be determined. In this study, we conducted site-directed mutagenesis of all residues located in the loops extending above blades 2 and 4 of the αIIb propeller, which are spatially close to, but distinct from, the loops that contain the binding site for an RGD ligand in the crystal structure of the αV propeller. Replacement by alanine of Q111, H112 or N114 in the loop within the blade 2 (the W2:2-3 loop in the propeller model) abolished binding of a ligand-mimetic antibody and fibrinogen to αIIbβ3 induced by different types of integrin activation including activation of αIIbβ3 by β3 cytoplasmic mutation. CHO cells stably expressing recombinant αIIbβ3 bearing Q111A, H112A or N114A mutation did not exhibit αIIbβ3mediated adhesion to fibrinogen. According to the crystal structure of αVβ3, the αV residue corresponding to αIIbN114 is exposed on the integrin surface and close to the RGD binding site. These results suggest that the Q111, H112 and N114 residues in the loop within blade 2 of the αIIb propeller are critical for ligand binding, possibly because of direct interaction with ligands or modulation of the RGD binding pocket.

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