5E88

Crystal structure of Human galectin-3 CRD in complex with thienyl-1,2,3-triazolyl thiodigalactoside inhibitor

Summary for 5E88

• Entry DOI: 10.2210/pdb5e88/pdb
• Related: 5E89 5E8A
• Descriptor: Galectin-3, CHLORIDE ION, 3-deoxy-3-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]-beta-D-galactopyranosyl 3-deoxy-1-thio-3-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]-beta-D-galactopyranoside, ... (4 entities in total)
• Functional Keywords: carbohydrate-recognition, beta sandwich, carbohydrate binding protein, sugar binding protein, sugar binding protein-inhibitor complex, sugar binding protein/inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P17931
• Total number of polymer chains: 1
• Total formula weight: 16418.26

Authors

Collins, P.M.,Blanchard, H. (deposition date: 2015-10-13, release date: 2016-08-24, Last modification date: 2023-09-27)

Primary citation

Delaine, T.,Collins, P.,MacKinnon, A.,Sharma, G.,Stegmayr, J.,Rajput, V.K.,Mandal, S.,Cumpstey, I.,Larumbe, A.,Salameh, B.A.,Kahl-Knutsson, B.,van Hattum, H.,van Scherpenzeel, M.,Pieters, R.J.,Sethi, T.,Schambye, H.,Oredsson, S.,Leffler, H.,Blanchard, H.,Nilsson, U.J.
Galectin-3-Binding Glycomimetics that Strongly Reduce Bleomycin-Induced Lung Fibrosis and Modulate Intracellular Glycan Recognition.
Chembiochem, 17:1759-1770, 2016

PubMed Abstract: Discovery of glycan-competitive galectin-3-binding compounds that attenuate lung fibrosis in a murine model and that block intracellular galectin-3 accumulation at damaged vesicles, hence revealing galectin-3-glycan interactions involved in fibrosis progression and in intracellular galectin-3 activities, is reported. 3,3'-Bis-(4-aryltriazol-1-yl)thiodigalactosides were synthesized and evaluated as antagonists of galectin-1, -2, -3, and -4 N-terminal, -4 C-terminal, -7 and -8 N-terminal, -9 N-terminal, and -9 C-terminal domains. Compounds displaying low-nanomolar affinities for galectins-1 and -3 were identified in a competitive fluorescence anisotropy assay. X-ray structural analysis of selected compounds in complex with galectin-3, together with galectin-3 mutant binding experiments, revealed that both the aryltriazolyl moieties and fluoro substituents on the compounds are involved in key interactions responsible for exceptional affinities towards galectin-3. The most potent galectin-3 antagonist was demonstrated to act in an assay monitoring galectin-3 accumulation upon amitriptyline-induced vesicle damage, visualizing a biochemically/medically relevant intracellular lectin-carbohydrate binding event and that it can be blocked by a small molecule. The same antagonist administered intratracheally attenuated bleomycin-induced pulmonary fibrosis in a mouse model with a dose/response profile comparing favorably with that of oral administration of the marketed antifibrotic compound pirfenidone.

PubMed: 27356186
DOI: 10.1002/cbic.201600285

Experimental method

X-RAY DIFFRACTION (1.6 Å)