5H9P: Crystal Structure Of Human Galectin-3 Crd In Complex With Td139

Citation:
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 muM to nM, is improved and also offer insights to development of selective inhibitors for individual galectins.
PDB ID: 5H9PDownload
MMDB ID: 140529
PDB Deposition Date: 2015/12/29
Updated in MMDB: 2016/08
Experimental Method:
x-ray diffraction
Resolution: 2.04  Å
Source Organism:
Similar Structures:
Biological Unit for 5H9P: monomeric; determined by author and by software (PISA)
Molecular Components in 5H9P
Label Count Molecule
Protein (1 molecule)
1
Galectin-3(Gene symbol: LGALS3)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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