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. 2019 May 27;58(22):7268-7272.
doi: 10.1002/anie.201900723. Epub 2019 Apr 17.

Minimizing the Entropy Penalty for Ligand Binding: Lessons from the Molecular Recognition of the Histo Blood-Group Antigens by Human Galectin-3

Ana Gimeno  1 , Sandra Delgado  1 , Pablo Valverde  1 , Sara Bertuzzi  1 , Manuel Alvaro Berbís  2 , Javier Echavarren  2 , Alessandra Lacetera  2 , Sonsoles Martín-Santamaría  2 , Avadhesha Surolia  3 , Francisco Javier Cañada  2 , Jesus Jiménez-Barbero  1   4   5 , Ana Ardá  1
Affiliations

Minimizing the Entropy Penalty for Ligand Binding: Lessons from the Molecular Recognition of the Histo Blood-Group Antigens by Human Galectin-3

Ana Gimeno et al. Angew Chem Int Ed Engl. .

Abstract

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.

Keywords: blood-group antigen; conformational entropy; glycans; lectins; molecular recognition.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Glycan structures used in this study. Yellow circle: galactose (Gal), blue square: glucosamine (GlcNAc), red triangle: fucose (Fuc), yellow square: galactosamine (GalNAc).
Figure 1
Figure 1
A) 1H‐STD‐NMR spectra and epitope map for the interaction of 4 with hGal‐3. B) STD epitope mapping of sugars 2, 3, and 5.
Figure 2
Figure 2
A, B) Chemical‐shift perturbations for the backbone amides of hGal‐3 upon addition of 2 (A, green) and 4 (B, blue) compared to LacNAc (black). For 3 and 5, see the Supporting Information. C) Molecular models for the complexes of hGal‐3 with 2 (green), 3 (orange), 4 (blue), and 5 (purple).
Figure 3
Figure 3
Thermodynamic profiles for the interaction of 1–5 with hGal‐3, as measured by ITC experiments.
Figure 4
Figure 4
A) 2D‐NMR trROESY spectrum of 1:10 hGal‐3/4. B) MD‐derived structure of the hGal‐3/B‐BGA (4) complex.
Figure 5
Figure 5
MD‐based conformational analysis of 3–5 in the free and bound states.
See this image and copyright information in PMC

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