9fdc: Difference between revisions

Latest revision as of 09:20, 4 June 2025

Co-crystal structure of Galectin-3 with an inhibitor

Structural highlights

9fdc is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.78Å
Ligands:	2PE, A1IB4, SCN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LEG3_HUMAN 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 (By similarity). 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.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Galectin-3 (Gal-3), a beta-galactoside-binding lectin, is implicated in diverse cellular functions ranging from immune response modulation to tissue homeostasis. Notably, increased Gal-3 expression has been linked to the progression of numerous diseases, including cancer, fibrosis, and cardiovascular disorders, underscoring its potential as a therapeutic target. Small molecule inhibitors have been discovered and are valuable tools to study such diseases. We report here the discovery of novel, galactose-based, small molecule inhibitors such as compound 12 which are orally bioavailable and show efficacy in a mouse model of acute liver injury and fibrosis (CCl4 model). The use of structure-based drug design (docking of a virtual library of amides based on acid 2) was key in the process towards potent, nanomolar inhibitors.

, PMID:40071533^[4]

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:https://dx.doi.org/10.1091/mbc.E04-03-0236
↑ Henderson NC, Sethi T. The regulation of inflammation by galectin-3. Immunol Rev. 2009 Jul;230(1):160-71. doi: 10.1111/j.1600-065X.2009.00794.x. PMID:19594635 doi:10.1111/j.1600-065X.2009.00794.x
↑ Haudek KC, Spronk KJ, Voss PG, Patterson RJ, Wang JL, Arnoys EJ. Dynamics of galectin-3 in the nucleus and cytoplasm. Biochim Biophys Acta. 2010 Feb;1800(2):181-189. Epub 2009 Jul 16. PMID:19616076 doi:S0304-4165(09)00194-9
↑ Zumbrunn C, Remen L, Sager CP, Grisostomi C, Stamm C, Krüsi D, Glutz S, Schmidt G, Nayler O, Iglarz M, Mac Sweeney A, Chambovey A, Müller M, Mueller C, Hühn E, Cattaneo C, Vercauteren M, Gatfield J, Bolli MH, Meyer S, Bourquin G. Discovery of Galactopyranose-1-Carboxamides as a New Class of Small, Novel, Potent, Selective, and Orally Active Galectin-3 Inhibitors. ChemMedChem. 2025 Mar 12:e202401012. PMID:40071533 doi:10.1002/cmdc.202401012

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OCA

[1] 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:https://dx.doi.org/10.1091/mbc.E04-03-0236

[2] Henderson NC, Sethi T. The regulation of inflammation by galectin-3. Immunol Rev. 2009 Jul;230(1):160-71. doi: 10.1111/j.1600-065X.2009.00794.x. PMID:19594635 doi:10.1111/j.1600-065X.2009.00794.x

[3] Haudek KC, Spronk KJ, Voss PG, Patterson RJ, Wang JL, Arnoys EJ. Dynamics of galectin-3 in the nucleus and cytoplasm. Biochim Biophys Acta. 2010 Feb;1800(2):181-189. Epub 2009 Jul 16. PMID:19616076 doi:S0304-4165(09)00194-9

[4] Zumbrunn C, Remen L, Sager CP, Grisostomi C, Stamm C, Krüsi D, Glutz S, Schmidt G, Nayler O, Iglarz M, Mac Sweeney A, Chambovey A, Müller M, Mueller C, Hühn E, Cattaneo C, Vercauteren M, Gatfield J, Bolli MH, Meyer S, Bourquin G. Discovery of Galactopyranose-1-Carboxamides as a New Class of Small, Novel, Potent, Selective, and Orally Active Galectin-3 Inhibitors. ChemMedChem. 2025 Mar 12:e202401012. PMID:40071533 doi:10.1002/cmdc.202401012

[1]

[2]

[3]

[4]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9fdc is ON HOLD
+==Co-crystal structure of Galectin-3 with an inhibitor==
+<StructureSection load='9fdc' size='340' side='right'caption='[[9fdc]], [[Resolution|resolution]] 1.78&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9fdc]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9FDC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9FDC 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]] 1.78&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2PE:NONAETHYLENE+GLYCOL'>2PE</scene>, <scene name='pdbligand=A1IB4:(2~{R},3~{R},4~{S},5~{R},6~{R})-~{N}-[3,5-bis(chloranyl)phenyl]-6-(hydroxymethyl)-~{N}-methyl-3,5-bis(oxidanyl)-4-[4-[3,4,5-tris(fluoranyl)phenyl]-1,2,3-triazol-1-yl]oxane-2-carboxamide'>A1IB4</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</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=9fdc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9fdc OCA], [https://pdbe.org/9fdc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9fdc RCSB], [https://www.ebi.ac.uk/pdbsum/9fdc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9fdc ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/LEG3_HUMAN LEG3_HUMAN] 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 (By similarity). 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.<ref>PMID:15181153</ref> <ref>PMID:19594635</ref> <ref>PMID:19616076</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Galectin-3 (Gal-3), a beta-galactoside-binding lectin, is implicated in diverse cellular functions ranging from immune response modulation to tissue homeostasis. Notably, increased Gal-3 expression has been linked to the progression of numerous diseases, including cancer, fibrosis, and cardiovascular disorders, underscoring its potential as a therapeutic target. Small molecule inhibitors have been discovered and are valuable tools to study such diseases. We report here the discovery of novel, galactose-based, small molecule inhibitors such as compound 12 which are orally bioavailable and show efficacy in a mouse model of acute liver injury and fibrosis (CCl4 model). The use of structure-based drug design (docking of a virtual library of amides based on acid 2) was key in the process towards potent, nanomolar inhibitors.
-Authors:
+,  PMID:40071533<ref>PMID:40071533</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 9fdc" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Mac Sweeney A]]

9fdc: Difference between revisions

Latest revision as of 09:20, 4 June 2025

Co-crystal structure of Galectin-3 with an inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

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