7CXA

Structure of human Galectin-3 CRD in complex with TD-139 belonging to P31 space group.

Summary for 7CXA

• Entry DOI: 10.2210/pdb7cxa/pdb
• Related: 7CXB 7CXC 7CXD
• Descriptor: Galectin-3, CHLORIDE ION, 3-deoxy-3-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-beta-D-galactopyranosyl 3-deoxy-3-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-beta-D-galactopyranoside, ... (4 entities in total)
• Functional Keywords: beta-galactose binding protein, carbohydrate, sugar binding protein, td-139
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 38498.50

Authors

Kumar, A. (deposition date: 2020-09-01, release date: 2021-09-01, Last modification date: 2023-11-29)

Primary citation

Kumar, A.,Paul, M.,Panda, M.,Jayaram, S.,Kalidindi, N.,Sale, H.,Vetrichelvan, M.,Gupta, A.,Mathur, A.,Beno, B.,Regueiro-Ren, A.,Cheng, D.,Ramarao, M.,Ghosh, K.
Molecular mechanism of interspecies differences in the binding affinity of TD139 to Galectin-3.
Glycobiology, 31:1390-1400, 2021

PubMed Abstract: Galectin-3 (Gal-3), a β-galactoside-binding lectin, has been implicated in a plethora of pathological disorders including fibrosis, inflammation, cancer and metabolic diseases. TD139-a thio-digalactoside inhibitor developed by Galecto Biotech as a potential therapeutic for idiopathic pulmonary fibrosis-is the most advanced small-molecule Gal-3 inhibitor in clinical studies. It binds to human Gal-3 with high affinity but has lower affinity towards mouse and rat homologs, which is also manifested in the differential inhibition of Gal-3 function. Using biophysical methods and high-resolution X-ray co-crystal structures of TD139 and Gal-3 proteins, we demonstrate that a single amino acid change corresponding to A146 in human Gal-3 is sufficient for the observed reduction in the binding affinity of TD139 in rodents. Site-directed mutagenesis of A146V (in human Gal-3) and V160A (in mouse Gal-3) was sufficient to interchange the affinities, mainly by affecting the off rates of the inhibitor binding. In addition, molecular dynamics simulations of both wild-type and mutant structures revealed the sustained favorable noncovalent interactions between the fluorophenyl ring and the active site A146 (human Gal-3 and mouse V160A) that corroborate the finding from biophysical studies. Current findings have ramifications in the context of optimization of drug candidates against Gal-3.

PubMed: 34228782
DOI: 10.1093/glycob/cwab072

Experimental method

X-RAY DIFFRACTION (1.97 Å)