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Minimizing the Entropy Penalty for Ligand Binding: Lessons from the Molecular Recognition of the Histo Blood‐Group Antigens by Human Galectin‐3
Author(s) -
Gimeno Ana,
Delgado Sandra,
Valverde Pablo,
Bertuzzi Sara,
Berbís Manuel Alvaro,
Echavarren Javier,
Lacetera Alessandra,
MartínSantamaría Sonsoles,
Surolia Avadhesha,
Cañada Francisco Javier,
JiménezBarbero Jesus,
Ardá Ana
Publication year - 2019
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201900723
Subject(s) - conformational entropy , glycan , chemistry , glycosidic bond , entropy (arrow of time) , galectin , fucose , stereochemistry , molecular recognition , biochemistry , computational biology , biophysics , galactose , molecule , biology , thermodynamics , glycoprotein , enzyme , physics , organic chemistry
Ligand conformational entropy plays an important role in carbohydrate recognition events. Glycans are characterized by intrinsic flexibility around the glycosidic linkages, thus in most cases, loss of conformational entropy of the sugar upon complex formation strongly affects the entropy of the binding process. By employing a multidisciplinary approach combining structural, conformational, binding energy, and kinetic information, we investigated the role of conformational entropy in the recognition of the histo blood‐group antigens A and B by human galectin‐3, a lectin of biomedical interest. We show that these rigid natural antigens are pre‐organized ligands for hGal‐3, and that restriction of the conformational flexibility by the branched fucose (Fuc) residue modulates the thermodynamics and kinetics of the binding process. These results highlight the importance of glycan flexibility and provide inspiration for the design of high‐affinity ligands as antagonists for lectins.