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7cxc

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Structure of mouse Galectin-3 CRD point mutant (V160A) in complex with TD-139 belonging to P121 space group.

Structural highlights

7cxc is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.4Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LEG3_MOUSE Galactose-specific lectin which binds IgE. May mediate with the alpha-3, beta-1 integrin the stimulation by CSPG4 of endothelial cells migration. Together with DMBT1, required for terminal differentiation of columnar epithelial cells during early embryogenesis. In the nucleus: acts as a pre-mRNA splicing factor. Involved in acute inflammatory responses including neutrophil activation and adhesion, chemoattraction of monocytes macrophages, opsonization of apoptotic neutrophils, and activation of mast cells. Together with TRIM16, coordinates the recognition of membrane damage with mobilization of the core autophagy regulators ATG16L1 and BECN1 in response to damaged endomembranes.^[1]

Publication Abstract from PubMed

Galectin-3 (Gal-3), a beta-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.

Molecular mechanism of interspecies differences in the binding affinity of TD139 to Galectin-3.,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 Glycobiology. 2021 Nov 18;31(10):1390-1400. doi: 10.1093/glycob/cwab072. PMID:34228782^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Fukushi J, Makagiansar IT, Stallcup WB. NG2 proteoglycan promotes endothelial cell motility and angiogenesis via engagement of galectin-3 and alpha3beta1 integrin. Mol Biol Cell. 2004 Aug;15(8):3580-90. Epub 2004 Jun 4. PMID:15181153 doi:http://dx.doi.org/10.1091/mbc.E04-03-0236
↑ 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. 2021 Nov 18;31(10):1390-1400. PMID:34228782 doi:10.1093/glycob/cwab072