5E8A

Crystal structure of Human galectin-3 CRD in complex with 4-fluophenyl-1,2,3-triazolyl thiodigalactoside inhibitor

5E8A の概要

• エントリーDOI: 10.2210/pdb5e8a/pdb
• 関連するPDBエントリー: 5E88 5E89
• 分子名称: Galectin-3, CHLORIDE ION, 3-deoxy-3-[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]-beta-D-galactopyranosyl 3-deoxy-3-[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-beta-D-galactopyranoside, ... (4 entities in total)
• 機能のキーワード: carbohydrate-recognition, beta sandwich, carbohydrate binding protein, sugar binding protein, inhibitor, sugar binding protein-inhibitor complex, sugar binding protein/inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: P17931
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 16442.19

構造登録者

Collins, P.M.,Blanchard, H. (登録日: 2015-10-13, 公開日: 2016-08-24, 最終更新日: 2023-09-27)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.5 Å)