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

EMILIANO D. PRIMO; WALTER GIORDANO; SEBASTIÁN KLINKE; KARINA V. MARIÑO; ALEJANDRO J. CAGNONI; MARÍA EMILIA CANO

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2020 vol. 76 p. 1080 - 1091

0907-4449

Carbohydrate-lectin interactions are involved in important cellular recognition processes,including viral and bacterial infections, inflammation, and tumor metastasis. Hence, thestructural studies of lectin-synthetic glycan complexes are essential for understanding thelectin recognition processes and the further design of promising chemotherapeutics thatinterfere with sugar-lectin interactions.Plant lectins are excellent models for the study of the molecular recognition process. Amongthem, peanut lectin (PNA) is highly relevant in the glycobiology field, because of its specificityfor β-galactosides, showing high affinity towards the Thomsen-Friedenreich (TF) antigen, awell-known tumor-associated carbohydrate antigen. Given this specificity, PNA is one of themost 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. Herein, crystal structures of PNA are reported incomplex with six novel synthetic hydrolytically stable β-N- and β-S-galactosides. Thesecomplexes disclosed key molecular binding interactions of the different sugars to PNA at theatomic level, revealing the role of specific water molecules in the protein?ligand recognition.Furthermore, binding affinity studies measured by isothermal titration calorimetry showeddissociation constant values in the micromolar range, as well as a positive multivalencyeffect in terms of affinity in the case of the divalent compounds. Taken together, this workprovides qualitative structural rationale for the upcoming synthesis of optimizedglycoclusters, designed for the study of lectin-mediated biological processes. Theunderstanding of the recognition of β-N- and β-S-galactosides with PNA represents abenchmark in protein-carbohydrate interactions since they are novel synthetic ligands notbelonging to the family of O-linked glycosides.