31NP

Crystal structure of the complex of galectin-8N-2,6-anhydro-3-deoxy-3-S-(beta-D-galactopyranosyl)-3-thio-D-glycero-L-altro-heptonamide

This is a non-PDB format compatible entry.

Summary for 31NP

• Entry DOI: 10.2210/pdb31np/pdb
• Related: 31ML
• Descriptor: Galectin-8, GLYCEROL, 1-thio-beta-D-galactopyranose, ... (5 entities in total)
• Functional Keywords: galectin-8n, sugar binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 36441.64

Authors

Tsagkarakou, A.S.,Kantsadi, A.L.,Leonidas, D.D. (deposition date: 2026-06-15, release date: 2026-08-26)

Primary citation

Tsagkarakou, A.S.,Kantsadi, A.L.,Theodoridou, V.I.,Veliotis, N.,Lazar, L.,Jozsef, J.,Juhasz, L.,Kontopidis, G.,Leffler, H.,Nilsson, U.J.,Somsak, L.,Leonidas, D.D.
Structural and Biophysical Characterization of C-Glycosylic 1,2-Thiodisaccharides Reveals Determinants of Selective Binding to Galectin-7 and Galectin-8N.
Chemmedchem, 21:e70439-e70439, 2026

PubMed Abstract: Achieving isoform selectivity within the galectin family remains a central challenge in glycomimetic drug design due to the highly conserved architecture of their carbohydrate recognition domains. Here, we define the structural and thermodynamic basis of recognition of a series of C-glycosylic 1,2-thiodisaccharides targeting human galectin-7 and the N-terminal domain of galectin-8 (galectin-8N). Using an integrated approach combining fluorescence polarization, isothermal titration calorimetry, and high-resolution X-Ray crystallography, we establish a clear structure-activity relationship across the ligand series. Compound 17 emerges as the most potent galectin-8N ligand (K = 13 μM), outperforming thiodigalactoside, while compound 13 shows preferential binding to galectin-7, demonstrating tunable isoform bias. Structural analysis reveals a conserved anchoring mechanism in which the β-galactoside unit (Gly-1) drives affinity through a rigid hydrogen-bonding and π-stacking network, whereas the second sugar (Gly-2) modulates potency by adopting distinct orientations in galectin-specific extended binding sites. Notably, ligand binding converges on conserved motifs while leaving nonconserved regions unexploited, highlighting clear opportunities for structure-guided optimization. Collectively, this work establishes C-glycosylic thiodisaccharides as a robust platform for selective galectin targeting and provides actionable design principles for next-generation inhibitors.

PubMed: 42603778
DOI: 10.1002/cmdc.70439

Experimental method

X-RAY DIFFRACTION (1.78 Å)