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Structural basis for langerin recognition of diverse pathogen and mammalian glycans through a single binding site.

Feinberg H, Taylor ME, Razi N, McBride R, Knirel YA, Graham SA, Drickamer K, Weis WI - J. Mol. Biol. (2010)

Bottom Line: The fucose moiety of the blood group B trisaccharide Galα1-3(Fucα1-2)Gal also binds to the Ca(2+) site, and selective binding to this glycan compared to other fucose-containing oligosaccharides results from additional favorable interactions of the nonreducing terminal galactose, as well as of the fucose residue.Surprisingly, the equatorial 3-OH group and the axial 4-OH group of the galactose residue in 6SO(4)-Galβ1-4GlcNAc also coordinate Ca(2+), a heretofore unobserved mode of galactose binding in a C-type carbohydrate-recognition domain bearing the Glu-Pro-Asn signature motif characteristic of mannose binding sites.Salt bridges between the sulfate group and two lysine residues appear to compensate for the nonoptimal binding of galactose at this site.

View Article: PubMed Central - PubMed

Affiliation: Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.

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Structure of the CRD of langerin bound to the blood group B trisaccharide. The color scheme is the same as that described in Fig. 2. (a) Overall structure of protomer A bound to the trisaccharide. (b) Top: Diagram of the blood group B trisaccharide showing linkages between the sugars. Bottom: Fo − Fc electron density (3.0σ; cyan), calculated by omitting the trisaccharide model. (c and d) Fucose moiety bound at the Ca2+ binding site. (e) Terminal galactose moiety of the blood group B trisaccharide in the extended binding site. (f) Langerin carbohydrate-binding surface. Langerin CRD bound to the blood group B trisaccharide. The protein is shown in surface representation: residues not interacting with the carbohydrate (green), Ca2+ ligands (cyan), Lys299 (blue), and other residues interacting with the sugar (light brown). Ca2+ is shown in orange. (g) Model for Lewisx binding through hydroxyl groups 2 and 3 of fucose. The fucose moiety of Lewisx bound to DC-SIGN19 (PDB entry 1SL5) was superimposed on the fucose of the blood group B trisaccharide. Carbon atoms in the Lewisx trisaccharide are shown in cyan. (h) Model for Lewisx binding through hydroxyl groups 3 and 4 of fucose. The CRD of DC-SIGN bound to lacto-N-fucopentaose III (PDB entry 1SL5) was superimposed on the CRD of langerin. For simplicity, only the Lewisx moiety of lacto-N-fucopentaose III is shown (light blue). (i) Comparison of the two potential modes for fucose binding to the Ca2+ site. Fucose from the structure of langerin bound to the blood group B trisaccharide is shown in yellow, and fucose from the superposition described in (g) is shown in light blue.
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f0015: Structure of the CRD of langerin bound to the blood group B trisaccharide. The color scheme is the same as that described in Fig. 2. (a) Overall structure of protomer A bound to the trisaccharide. (b) Top: Diagram of the blood group B trisaccharide showing linkages between the sugars. Bottom: Fo − Fc electron density (3.0σ; cyan), calculated by omitting the trisaccharide model. (c and d) Fucose moiety bound at the Ca2+ binding site. (e) Terminal galactose moiety of the blood group B trisaccharide in the extended binding site. (f) Langerin carbohydrate-binding surface. Langerin CRD bound to the blood group B trisaccharide. The protein is shown in surface representation: residues not interacting with the carbohydrate (green), Ca2+ ligands (cyan), Lys299 (blue), and other residues interacting with the sugar (light brown). Ca2+ is shown in orange. (g) Model for Lewisx binding through hydroxyl groups 2 and 3 of fucose. The fucose moiety of Lewisx bound to DC-SIGN19 (PDB entry 1SL5) was superimposed on the fucose of the blood group B trisaccharide. Carbon atoms in the Lewisx trisaccharide are shown in cyan. (h) Model for Lewisx binding through hydroxyl groups 3 and 4 of fucose. The CRD of DC-SIGN bound to lacto-N-fucopentaose III (PDB entry 1SL5) was superimposed on the CRD of langerin. For simplicity, only the Lewisx moiety of lacto-N-fucopentaose III is shown (light blue). (i) Comparison of the two potential modes for fucose binding to the Ca2+ site. Fucose from the structure of langerin bound to the blood group B trisaccharide is shown in yellow, and fucose from the superposition described in (g) is shown in light blue.

Mentions: The bound blood group B trisaccharide was found to have the same orientation in all four CRDs in the asymmetric unit of the cocrystals. The fucose moiety binds to the Ca2+ site, with the equatorial 2-OH and 3-OH groups coordinating Ca2+ (Fig. 3a–c). In addition to the four Ca2+ ligands that form hydrogen bonds to the 2-OH and 3-OH groups of fucose, the 4-OH group forms a hydrogen bond with Lys299, and the ring 3-C packs against the side chain of Ala289 (Fig. 3c and d). The central galactose residue is positioned away from the protein, but the nonreducing galactose residue packs against Cα of Gly284 and the side chains of Ile282, Glu285, and Asn287. The 4-OH group of this galactose also forms a hydrogen bond with the backbone carbonyl oxygen of Pro283, and the 6-OH group is hydrogen bonded to the side-chain amide group of Asn287 (Fig. 3e and f). Since Asn287 also donates a hydrogen bond to the bound fucose, this residue bridges the fucose and galactose moieties (Fig. 3c and e). The 2-OH group of the nonreducing terminal galactose points away from the protein surface, explaining why the blood group A trisaccharide GalNAcα1–3(Fucα1–2)Gal can bind to langerin, albeit more weakly than the blood group B trisaccharide.


Structural basis for langerin recognition of diverse pathogen and mammalian glycans through a single binding site.

Feinberg H, Taylor ME, Razi N, McBride R, Knirel YA, Graham SA, Drickamer K, Weis WI - J. Mol. Biol. (2010)

Structure of the CRD of langerin bound to the blood group B trisaccharide. The color scheme is the same as that described in Fig. 2. (a) Overall structure of protomer A bound to the trisaccharide. (b) Top: Diagram of the blood group B trisaccharide showing linkages between the sugars. Bottom: Fo − Fc electron density (3.0σ; cyan), calculated by omitting the trisaccharide model. (c and d) Fucose moiety bound at the Ca2+ binding site. (e) Terminal galactose moiety of the blood group B trisaccharide in the extended binding site. (f) Langerin carbohydrate-binding surface. Langerin CRD bound to the blood group B trisaccharide. The protein is shown in surface representation: residues not interacting with the carbohydrate (green), Ca2+ ligands (cyan), Lys299 (blue), and other residues interacting with the sugar (light brown). Ca2+ is shown in orange. (g) Model for Lewisx binding through hydroxyl groups 2 and 3 of fucose. The fucose moiety of Lewisx bound to DC-SIGN19 (PDB entry 1SL5) was superimposed on the fucose of the blood group B trisaccharide. Carbon atoms in the Lewisx trisaccharide are shown in cyan. (h) Model for Lewisx binding through hydroxyl groups 3 and 4 of fucose. The CRD of DC-SIGN bound to lacto-N-fucopentaose III (PDB entry 1SL5) was superimposed on the CRD of langerin. For simplicity, only the Lewisx moiety of lacto-N-fucopentaose III is shown (light blue). (i) Comparison of the two potential modes for fucose binding to the Ca2+ site. Fucose from the structure of langerin bound to the blood group B trisaccharide is shown in yellow, and fucose from the superposition described in (g) is shown in light blue.
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Related In: Results  -  Collection

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Show All Figures
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f0015: Structure of the CRD of langerin bound to the blood group B trisaccharide. The color scheme is the same as that described in Fig. 2. (a) Overall structure of protomer A bound to the trisaccharide. (b) Top: Diagram of the blood group B trisaccharide showing linkages between the sugars. Bottom: Fo − Fc electron density (3.0σ; cyan), calculated by omitting the trisaccharide model. (c and d) Fucose moiety bound at the Ca2+ binding site. (e) Terminal galactose moiety of the blood group B trisaccharide in the extended binding site. (f) Langerin carbohydrate-binding surface. Langerin CRD bound to the blood group B trisaccharide. The protein is shown in surface representation: residues not interacting with the carbohydrate (green), Ca2+ ligands (cyan), Lys299 (blue), and other residues interacting with the sugar (light brown). Ca2+ is shown in orange. (g) Model for Lewisx binding through hydroxyl groups 2 and 3 of fucose. The fucose moiety of Lewisx bound to DC-SIGN19 (PDB entry 1SL5) was superimposed on the fucose of the blood group B trisaccharide. Carbon atoms in the Lewisx trisaccharide are shown in cyan. (h) Model for Lewisx binding through hydroxyl groups 3 and 4 of fucose. The CRD of DC-SIGN bound to lacto-N-fucopentaose III (PDB entry 1SL5) was superimposed on the CRD of langerin. For simplicity, only the Lewisx moiety of lacto-N-fucopentaose III is shown (light blue). (i) Comparison of the two potential modes for fucose binding to the Ca2+ site. Fucose from the structure of langerin bound to the blood group B trisaccharide is shown in yellow, and fucose from the superposition described in (g) is shown in light blue.
Mentions: The bound blood group B trisaccharide was found to have the same orientation in all four CRDs in the asymmetric unit of the cocrystals. The fucose moiety binds to the Ca2+ site, with the equatorial 2-OH and 3-OH groups coordinating Ca2+ (Fig. 3a–c). In addition to the four Ca2+ ligands that form hydrogen bonds to the 2-OH and 3-OH groups of fucose, the 4-OH group forms a hydrogen bond with Lys299, and the ring 3-C packs against the side chain of Ala289 (Fig. 3c and d). The central galactose residue is positioned away from the protein, but the nonreducing galactose residue packs against Cα of Gly284 and the side chains of Ile282, Glu285, and Asn287. The 4-OH group of this galactose also forms a hydrogen bond with the backbone carbonyl oxygen of Pro283, and the 6-OH group is hydrogen bonded to the side-chain amide group of Asn287 (Fig. 3e and f). Since Asn287 also donates a hydrogen bond to the bound fucose, this residue bridges the fucose and galactose moieties (Fig. 3c and e). The 2-OH group of the nonreducing terminal galactose points away from the protein surface, explaining why the blood group A trisaccharide GalNAcα1–3(Fucα1–2)Gal can bind to langerin, albeit more weakly than the blood group B trisaccharide.

Bottom Line: The fucose moiety of the blood group B trisaccharide Galα1-3(Fucα1-2)Gal also binds to the Ca(2+) site, and selective binding to this glycan compared to other fucose-containing oligosaccharides results from additional favorable interactions of the nonreducing terminal galactose, as well as of the fucose residue.Surprisingly, the equatorial 3-OH group and the axial 4-OH group of the galactose residue in 6SO(4)-Galβ1-4GlcNAc also coordinate Ca(2+), a heretofore unobserved mode of galactose binding in a C-type carbohydrate-recognition domain bearing the Glu-Pro-Asn signature motif characteristic of mannose binding sites.Salt bridges between the sulfate group and two lysine residues appear to compensate for the nonoptimal binding of galactose at this site.

View Article: PubMed Central - PubMed

Affiliation: Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.

Show MeSH
Related in: MedlinePlus