View source for 7cxd


==Xray structure of rat Galectin-3 CRD in complex with TD-139 belonging to P121 space group==
<StructureSection load='7cxd' size='340' side='right'caption='[[7cxd]], [[Resolution|resolution]] 1.71&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7cxd]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CXD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CXD FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.71&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=TD2:3-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'>TD2</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7cxd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cxd OCA], [https://pdbe.org/7cxd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7cxd RCSB], [https://www.ebi.ac.uk/pdbsum/7cxd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7cxd ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/LEG3_RAT LEG3_RAT] Galactose-specific lectin which binds IgE. May mediate with the alpha-3, beta-1 integrin the stimulation by CSPG4 of endothelial cells migration. 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 (By similarity). Together with DMBT1, required for terminal differentiation of columnar epithelial cells during early embryogenesis.<ref>PMID:11121438</ref> 
<div style="background-color:#fffaf0;">
== 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<ref>PMID:34228782</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7cxd" style="background-color:#fffaf0;"></div>

==See Also==
*[[Galectin 3D structures|Galectin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Rattus norvegicus]]
[[Category: Kumar A]]