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Crystal structures of peanut lectin in the presence of synthetic beta-N- and beta-S-galactosides disclose evidence for the recognition of different glycomimetic ligands

Abstract : Carbohydrate-lectin interactions are involved in important cellular recognition processes, including viral and bacterial infections, inflammation and tumor metastasis. Hence, structural studies of lectin-synthetic glycan complexes are essential for understanding lectin-recognition processes and for the further design of promising chemotherapeutics that interfere with sugar-lectin interactions. Plant lectins are excellent models for the study of the molecular-recognition process. Among them, peanut lectin (PNA) is highly relevant in the field of glycobiology because of its specificity for beta-galactosides, showing high affinity towards the Thomsen-Friedenreich antigen, a well known tumor-associated carbohydrate antigen. Given this specificity, PNA is one of the most frequently used molecular probes for the recognition of tumor cell-surface O-glycans. Thus, it has been extensively used in glycobiology for inhibition studies with a variety of beta-galactoside and beta-lactoside ligands. Here, crystal structures of PNA are reported in complex with six novel synthetic hydrolytically stable beta-N- and beta-S-galactosides. These complexes disclosed key molecular-binding interactions of the different sugars with PNA at the atomic level, revealing the roles of specific water molecules in protein-ligand recognition. Furthermore, binding-affinity studies by isothermal titration calorimetry showed dissociation-constant values in the micromolar range, as well as a positive multivalency effect in terms of affinity in the case of the divalent compounds. Taken together, this work provides a qualitative structural rationale for the upcoming synthesis of optimized glycoclusters designed for the study of lectin-mediated biological processes. The understanding of the recognition of beta-N- and beta-S-galactosides by PNA represents a benchmark in protein-carbohydrate interactions since they are novel synthetic ligands that do not belong to the family of O-linked glycosides.
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https://hal-u-picardie.archives-ouvertes.fr/hal-03613820
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Soumis le : vendredi 18 mars 2022 - 17:47:16
Dernière modification le : vendredi 5 août 2022 - 11:24:58

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Alejandro J. Cagnoni, Emiliano D. Primo, Sebastian Klinke, Maria E. Cano, Walter Giordano, et al.. Crystal structures of peanut lectin in the presence of synthetic beta-N- and beta-S-galactosides disclose evidence for the recognition of different glycomimetic ligands. Acta crystallographica Section D : Structural biology [1993-..], International Union of Crystallography, 2020, 76 (11), pp.1080-1091. ⟨10.1107/S2059798320012371⟩. ⟨hal-03613820⟩

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