Jayaprakash, NG and Singh, A and Vivek, R and Yadav, S and Pathak, S and Trivedi, J and Jayaraman, N and Nandi, D and Mitra, D and Surolia, A (2020) The barley lectin, horcolin, binds high-mannose glycans in a multivalent fashion, enabling high-affinity, specific inhibition of cellular HIV infection. In: Journal of Biological Chemistry, 295 (34). pp. 12111-12129.
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Abstract
N-Linked glycans are critical to the infection cycle of HIV, and most neutralizing antibodies target the high-mannose glycans found on the surface envelope glycoprotein-120 (gp120). Carbohydrate-binding proteins, particularly mannose-binding lectins, have also been shown to bind these glycans. Despite their therapeutic potency, their ability to cause lymphocyte proliferation limits their application. In this study, we report one such lectin named horcolin (Hordeum vulgare lectin), seen to lack mitogenicity owing to the divergence in the residues at its carbohydrate-binding sites, which makes it a promising candidate for exploration as an anti-HIV agent. Extensive isothermal titration calorimetry experiments reveal that the lectin was sensitive to the length and branching of mannooligosaccharides and thereby the total valency. Modeling and simulation studies demonstrate two distinct modes of binding, a monovalent binding to shorter saccharides and a bivalent mode for higher glycans, involving simultaneous interactions of multiple glycan arms with the primary carbohydrate-binding sites. This multivalent mode of binding was further strengthened by interactions of core mannosyl residues with a secondary conserved site on the protein, leading to an exponential increase in affinity. Finally, we confirmed the interaction of horcolin with recombinant gp120 and gp140 with high affinity and inhibition of HIV infection at nanomolar concentrations without mitogenicity. © 2019 Jayaprakash et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
| Item Type: | Journal Article |
|---|---|
| Publication: | Journal of Biological Chemistry |
| Publisher: | American Society for Biochemistry and Molecular Biology Inc. |
| Additional Information: | The copyright for this article belongs to Author(s). |
| Keywords: | Cell proliferation; Polysaccharides; Proteins, Envelope glycoproteins; Exponential increase; Isothermal titration calorimetry; Lymphocyte proliferation; Mannose binding lectins; Model and simulation; Nanomolar concentration; Neutralizing antibodies, Binding sites, antivirus agent; glycan; glycoprotein gp 120; glycoprotein gp 140; horcolin; lectin; mannose; mannose oligosaccharide; unclassified drug; glycoprotein gp 120; gp140 envelope protein, Human immunodeficiency virus 1; mannose; plant lectin; polysaccharide; virus envelope protein, animal cell; antiviral activity; Article; barley; binding affinity; binding site; controlled study; Human immunodeficiency virus infection; isothermal titration calorimetry; male; mitogenicity; molecular dynamics; mouse; nonhuman; priority journal; protein binding; protein interaction; thermodynamics; animal; chemistry; genetics; HEK293 cell line; Hordeum; human; Human immunodeficiency virus 1; Leporidae; metabolism, Animals; env Gene Products, Human Immunodeficiency Virus; HEK293 Cells; HIV Envelope Protein gp120; HIV Infections; HIV-1; Hordeum; Humans; Male; Mannose; Mice; Plant Lectins; Polysaccharides; Rabbits |
| Department/Centre: | Division of Biological Sciences > Biochemistry Division of Biological Sciences > Molecular Biophysics Unit Division of Chemical Sciences > Organic Chemistry |
| Date Deposited: | 13 Jan 2023 06:31 |
| Last Modified: | 13 Jan 2023 06:31 |
| URI: | https://eprints.iisc.ac.in/id/eprint/79099 |
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