title: Dual thio-digalactoside-binding modes of human galectins as the structural basis for the design of potent and selective inhibitors.
abstract: Human galectins are promising targets for cancer immunotherapeutic and fibrotic disease-related drugs. We report herein the binding interactions of three thio-digalactosides (TDGs) including TDG itself, TD139 (3,3'-deoxy-3,3'-bis-(4-[m-fluorophenyl]-1H-1,2,3-triazol-1-yl)-thio-digalactoside, recently approved for the treatment of idiopathic pulmonary fibrosis), and TAZTDG (3-deoxy-3-(4-[m-fluorophenyl]-1H-1,2,3-triazol-1-yl)-thio-digalactoside) with human galectins-1, -3 and -7 as assessed by X-ray crystallography, isothermal titration calorimetry and NMR spectroscopy. Five binding subsites (A-E) make up the carbohydrate-recognition domains of these galectins. We identified novel interactions between an arginine within subsite E of the galectins and an arene group in the ligands. In addition to the interactions contributed by the galactosyl sugar residues bound at subsites C and D, the fluorophenyl group of TAZTDG preferentially bound to subsite B in galectin-3, whereas the same group favored binding at subsite E in galectins-1 and -7. The characterised dual binding modes demonstrate how binding potency, reported as decreased Kd values of the TDG inhibitors from μM to nM, is improved and also offer insights to development of selective inhibitors for individual galectins.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, 11529, Taiwan.
authors.forename: Tung-Ju
authors.initials: TJ
authors.lastname: Hsieh
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, 11529, Taiwan.|Department of Chemistry, National Taiwan University, Taipei, 10617, Taiwan.
authors.forename: Hsien-Ya
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, 11529, Taiwan.
authors.forename: Zhijay
authors.initials: Z
authors.lastname: Tu
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, 11529, Taiwan.|Department of Chemistry, National Taiwan University, Taipei, 10617, Taiwan.
authors.forename: Ting-Chien
authors.initials: TC
authors.lastname: Lin
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, 11529, Taiwan.|Institute of Biochemical Sciences, National Taiwan University, Taipei, 10617, Taiwan.
authors.forename: Shang-Chuen
authors.initials: SC
authors.lastname: Wu
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, 11529, Taiwan.
authors.forename: Yu-Yao
authors.initials: YY
authors.lastname: Tseng
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan.
authors.forename: Fu-Tong
authors.initials: FT
authors.lastname: Liu
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, 11529, Taiwan.|Institute of Biochemical Sciences, National Taiwan University, Taipei, 10617, Taiwan.
authors.forename: Shang-Te Danny
authors.initials: ST
authors.lastname: Hsu
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, 11529, Taiwan.|Department of Chemistry, National Taiwan University, Taipei, 10617, Taiwan.|Institute of Biochemical Sciences, National Taiwan University, Taipei, 10617, Taiwan.|The Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan.
authors.forename: Chun-Hung
authors.initials: CH
authors.lastname: Lin
mesh_terms: D001665:Binding Sites; D001798:Blood Proteins; D002151:Calorimetry; D018360:Crystallography, X-Ray; D015195:Drug Design; D005697:Galactosides / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D037483:Galectin 1 / Q000737:chemistry; D037502:Galectin 3 / Q000737:chemistry; D037161:Galectins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D001798:Blood Proteins; D005697:Galactosides; D037483:Galectin 1; D037502:Galectin 3; D037161:Galectins; C445499:LGALS1 protein, human; C428445:LGALS3 protein, human; C092525:LGALS7 protein, human; D008024:Ligands; D011994:Recombinant Proteins