期刊
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
卷 76, 期 -, 页码 1080-1091出版社
INT UNION CRYSTALLOGRAPHY
DOI: 10.1107/S2059798320012371
关键词
carbohydrate– protein interactions; peanut agglutinin; glycoclusters; multivalent ligands; lectin structure; X‐ ray crystallography; isothermal titration calorimetry
资金
- Agencia Nacional de Promocion Cientifica y Tecnologica (ANPCyT) [PICT 2015-0621, PICT 2016-1425]
- Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET)
- Universidad de Buenos Aires (UBA), Argentina
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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