Symmetric dithiodigalactoside: strategic combination of binding studies and detection of selectivity between a plant toxin and human lectins
Autor: | Rémi Caraballo, F. Javier Cañada, Beatriz de Pascual-Teresa, Gloria Fernández-Cureses, João P. Ribeiro, Eliza Buzamet, Maria Morando, Jesús Jiménez-Barbero, Dolores Solís, Karla Ramírez-Gualito, Olof Ramström, Sabine André, Margarita Menéndez, Sonsoles Martín-Santamaría, Hans-Joachim Gabius |
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Rok vydání: | 2011 |
Předmět: |
Viscum album
Mistletoe Lectin Molecular Dynamics Simulation 010402 general chemistry medicine.disease_cause 01 natural sciences Biochemistry Models Biological Molecular-Dymnamics Simulations Thiogalactosides Solid-Phase 03 medical and health sciences chemistry.chemical_compound Agglutinin Cell Line Tumor Lectins medicine Animals Humans Physical and Theoretical Chemistry Binding site Carbohydrate-Binding 030304 developmental biology Galectin Toxins Biological 0303 health sciences Binding Sites Human Galectin-3 Chemistry Toxin Organic Chemistry Isothermal titration calorimetry Nuclear magnetic resonance spectroscopy Plants 0104 chemical sciences 3. Good health Structural-Changes Epitope mapping Conformational analysis Galactose Flexible Ligand Docking Cattle Endogenous Lectins Conformer Selection |
Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Organic & Biomolecular Chemistry; Vol 9 Organic & Biomolecular Chemistry |
Popis: | 11 páginas, 8 figuras -- PAGS nrs. 5445-5455 Thioglycosides offer the advantage over O-glycosides to be resistant to hydrolysis. Based on initial evidence of this recognition ability for glycosyldisulfides by screening dynamic combinatorial libraries, we have now systematically studied dithiodigalactoside on a plant toxin (Viscum album agglutinin) and five human lectins (adhesion/growth-regulatory galectins with medical relevance e.g. in tumor progression and spread). Inhibition assays with surface-presented neoglycoprotein and in solution monitored by saturation transfer difference NMR spectroscopy, flanked by epitope mapping, as well as isothermal titration calorimetry revealed binding properties to VAA (K(a): 1560 +/- 20 M (1)). They were reflected by the structural model and the affinity on the level of toxin-exposed cells. In comparison, galectins were considerably less reactive, with intrafamily grading down to very minor reactivity for tandem-repeat-type galectins, as quantitated by radioassays for both domains of galectin-4. Model building indicated contact formation to be restricted to only one galactose moiety, in contrast to thiodigalactoside. The tested glycosyldisulfide exhibits selectivity between the plant toxin and the tested human lectins, and also between these proteins. Therefore, glycosyldisulfides have potential as chemical platform for inhibitor design. This work has been generously supported by grants CTQ2009-08536, SAF2008-00945, BFU2006-10288 and BFU2009-10052 from the Spanish Ministry, an EC Marie Curie Research Training Network grant (contract no. MRTN-CT-2005-019561), the EC research program GlycoHIT (contract ID 260600), the Verein zur Forderung des biologisch-technologischen Fortschritts in der Medizin e. V. and the CIBER of Respiratory Diseases (CIBERES), an initiative from the Spanish Institute of Health Carlos III (ISCIII). We thank Drs B. Friday and S. Namirha for inspiring discussions as well as M. V. Lopez-Moyano for excellent technical assistance. |
Databáze: | OpenAIRE |
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