INVESTIGADORES
MARIÑO Karina Valeria
artículos
Título:
Crystal structures of peanut lectin in the presence of synthetic β-N- And β-S-galactosides disclose evidence for the recognition of different glycomimetic ligands
Autor/es:
CAGNONI, ALEJANDRO J.; PRIMO, EMILIANO D.; KLINKE, SEBASTIÁN; CANO, MARIÁ E.; GIORDANO, WALTER; MARIÑO, KARINA V.; KOVENSKY, JOSÉ; GOLDBAUM, FERNANDO A.; UHRIG, MARIÁ LAURA; OTERO, LISANDRO H.
Revista:
Acta Crystallographica Section D: Structural Biology
Editorial:
International Union of Crystallography
Referencias:
Año: 2020 vol. 76 p. 1080 - 1091
Resumen:
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 β-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 β-galactoside and β-lactoside ligands. Here, crystal structures of PNA are reported in complex with six novel synthetic hydrolytically stable β-N- and β-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 β-N- and β-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.