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

CAGNONI, ALEJANDRO J.; PRIMO, EMILIANO D.; KLINKE, SEBASTIÁN; CANO, MARIA E.; GIORDANO, WALTER; MARIÑO, KARINA; KOVENSKY, JOSE; GOLDBAUM, FERNANDO A.; UHRIG, MARIA L.; OTERO, LISANDRO H. * (* CORRESPONDING AUTHOR)

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2020 vol. D76 p. 1080 - 1091

0907-4449

Carbohydrate-lectininteractions are involved in important cellular recognitionprocesses, including viral and bacterial infections, inflammation,and tumor metastasis. Hence, the structural studies oflectin-synthetic glycan complexes are essential for understanding thelectin recognition processes and the further design of promisingchemotherapeutics that interfere with sugar-lectin interactions.Plant lectins are excellent models for the study of the molecularrecognition process. Among them, peanut lectin (PNA) is highlyrelevant in the glycobiology field, because of its specificity forβ-galactosides, showing high affinity towards theThomsen-Friedenreich (TF) antigen, a well-known tumor-associatedcarbohydrate antigen. Given this specificity, PNA is one of the mostfrequently used molecular probes for the recognition of tumorcell-surface O-glycans. Thus, it has been extensively used inglycobiology for inhibition studies with a variety of β-galactosideand β-lactoside ligands. Herein, crystal structures of PNA arereported in complex with six novel synthetic hydrolytically stableβ-N- and β-S-galactosides. These complexes disclosed key molecularbinding interactions of the different sugars to PNA at the atomiclevel, revealing the role of specific water molecules in theprotein?ligand recognition. Furthermore, binding affinity studiesmeasured by isothermal titration calorimetry showed dissociationconstant values in the micromolar range, as well as a positivemultivalency effect in terms of affinity in the case of the divalentcompounds. Taken together, this work provides qualitative structuralrationale for the upcoming synthesis of optimized glycoclusters,designed for the study of lectin-mediated biological processes. Theunderstanding of the recognition of β-N- and β-S-galactosides withPNA represents a benchmark in protein-carbohydrateinteractions since they are novel synthetic ligands not belonging tothe family of O-linked glycosides.p { margin-bottom: 0.25cm; line-height: 115% }