5ODY

Galectin-3C in complex with dithiogalactoside derivative

Summary for 5ODY

• Entry DOI: 10.2210/pdb5ody/pdb
• Descriptor: Galectin-3, 5,6-bis(fluoranyl)-3-[[(2~{R},3~{S},4~{S},5~{R},6~{S})-2-(hydroxymethyl)-6-[(2~{S},3~{R},4~{S},5~{R},6~{R})-6-(hydroxymethyl)-3,5-bis(oxidanyl)-4-[4-[3,4,5-tris(fluoranyl)phenyl]-1,2,3-triazol-1-yl]oxan-2-yl]sulfanyl-3,5-bis(oxidanyl)oxan-4-yl]oxymethyl]chromen-2-one (3 entities in total)
• Functional Keywords: lectin, carbohydrate-binding protein, galactose-specific lectin 3, galactoside-binding protein, galbp, ige-6 binding protein, l-31, laminin-binding protein, lectin l-29, mac-2, sugar binding protein
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P17931
• Total number of polymer chains: 1
• Total formula weight: 16434.66

Authors

Kumar, R.,Peterson, K.,Nilsson, U.J.,Logan, D.T. (deposition date: 2017-07-07, release date: 2018-05-23, Last modification date: 2024-01-17)

Primary citation

Peterson, K.,Kumar, R.,Stenstrom, O.,Verma, P.,Verma, P.R.,Hakansson, M.,Kahl-Knutsson, B.,Zetterberg, F.,Leffler, H.,Akke, M.,Logan, D.T.,Nilsson, U.J.
Systematic Tuning of Fluoro-galectin-3 Interactions Provides Thiodigalactoside Derivatives with Single-Digit nM Affinity and High Selectivity.
J. Med. Chem., 61:1164-1175, 2018

PubMed Abstract: Symmetrical and asymmetrical fluorinated phenyltriazolyl-thiodigalactoside derivatives have been synthesized and evaluated as inhibitors of galectin-1 and galectin-3. Systematic tuning of the phenyltriazolyl-thiodigalactosides' fluoro-interactions with galectin-3 led to the discovery of inhibitors with exceptional affinities (K down to 1-2 nM) in symmetrically substituted thiodigalactosides as well as unsurpassed combination of high affinity (K 7.5 nM) and selectivity (46-fold) over galectin-1 for asymmetrical thiodigalactosides by carrying one trifluorphenyltriazole and one coumaryl moiety. Studies of the inhibitor-galectin complexes with isothermal titration calorimetry and X-ray crystallography revealed the importance of fluoro-amide interaction for affinity and for selectivity. Finally, the high affinity of the discovered inhibitors required two competitive titration assay tools to be developed: a new high affinity fluorescent probe for competitive fluorescent polarization and a competitive ligand optimal for analyzing high affinity galectin-3 inhibitors with competitive isothermal titration calorimetry.

PubMed: 29284090
DOI: 10.1021/acs.jmedchem.7b01626

Experimental method

X-RAY DIFFRACTION (1.149 Å)