8PPN
Galectin-3 carbohydrate recognition domain in complex with thiodigalactoside at 1.8 resolution
Summary for 8PPN
| Entry DOI | 10.2210/pdb8ppn/pdb |
| Related | 8OJI |
| Related PRD ID | PRD_900027 |
| Descriptor | Galectin-3, 1-thio-beta-D-galactopyranose-(1-1)-beta-D-galactopyranose, CHLORIDE ION, ... (5 entities in total) |
| Functional Keywords | sugar binding protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 16186.96 |
| Authors | Tsagkarakou, A.S.,Leonidas, D.D. (deposition date: 2023-07-07, release date: 2023-09-13, Last modification date: 2023-09-20) |
| Primary citation | Lazar, L.,Tsagkarakou, A.S.,Stravodimos, G.,Kontopidis, G.,Leffler, H.,Nilsson, U.J.,Somsak, L.,Leonidas, D.D. Strong Binding of C -Glycosylic1,2-Thiodisaccharides to Galectin-3─Enthalpy-Driven Affinity Enhancement by Water-Mediated Hydrogen Bonds. J.Med.Chem., 66:12420-12431, 2023 Cited by PubMed Abstract: Galectin-3 is involved in multiple pathways of many diseases, including cancer, fibrosis, and diabetes, and it is a validated pharmaceutical target for the development of novel therapeutic agents to address unmet medical needs. Novel 1,2-thiodisaccharides with a -glycosylic functionality were synthesized by the photoinitiated thiol-ene click reaction of -peracylated 1-C-substituted glycals and 1-thio-glycopyranoses. Subsequent global deprotection yielded test compounds, which were studied for their binding to human galectin-3 by fluorescence polarization and isothermal titration calorimetry to show low micromolar values. The best inhibitor displayed a value of 8.0 μM. An analysis of the thermodynamic binding parameters revealed that the binding Gibbs free energy (Δ) of the new inhibitors was dominated by enthalpy (Δ). The binding mode of the four most efficient 1,2-thiodisaccharides was also studied by X-ray crystallography that uncovered the unique role of water-mediated hydrogen bonds in conferring enthalpy-driven affinity enhancement for the new inhibitors. This 1,2-thiodisaccharide-type scaffold represents a new lead for galectin-3 inhibitor discovery and offers several possibilities for further development. PubMed: 37658813DOI: 10.1021/acs.jmedchem.3c00882 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
Download full validation report
