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Characterization and Carbohydrate Specificity of Pradimicin S
- Shahzad-ul-Hussan, Syed, Ghirlando, Rodolfo, Dogo-Isonagie, Cajetan I., Igarashi, Yasuhiro, Balzarini, Jan, Bewley, Carole A.
- Journal of the American Chemical Society 2012 v.134 no.30 pp. 12346-12349
- Human immunodeficiency virus 1, anti-infective properties, antibiotics, binding sites, calcium, glycoproteins, inhibitory concentration 50, mannose, models, nuclear magnetic resonance spectroscopy, oligomerization, trisaccharides, ultracentrifugation, water solubility
- The pradimicin family of antibiotics is attracting attention due to its anti-infective properties and as a model for understanding the requirements for carbohydrate recognition by small molecules. Members of the pradimicin family are unique among natural products in their ability to bind sugars in a Ca²⁺-dependent manner, but the oligomerization to insoluble aggregates that occurs upon Ca²⁺ binding has prevented detailed characterization of their carbohydrate specificity and biologically relevant form. Here we take advantage of the water solubility of pradimicin S (PRM-S), a sulfated glucose-containing analogue of pradimicin A (PRM-A), to show by NMR spectroscopy and analytical ultracentrifugation that at biologically relevant concentrations, PRM-S binds Ca²⁺ to form a tetrameric species that selectively binds and engulfs the trisaccharide Manα1–3(Manα1–6)Man over mannose or mannobiose. In functional HIV-1 entry assays, IC₅₀ values of 2–4 μM for PRM-S corrrelate with the concentrations at which oligomerization occurs as well as the affinities with which PRM-S binds the HIV surface envelope glycoprotein gp120. Together these data reveal the biologically active form of PRM-S, provide an explanation for previous speculations that PRM-A may contain a second mannose binding site, and expand our understanding of the characteristics that can engender a small molecule with the ability to function as a carbohydrate receptor.