7p1m: Difference between revisions
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==Galectin-8 N-terminal carbohydrate recognition domain in complex with benzimidazole D-galactal ligand== | ==Galectin-8 N-terminal carbohydrate recognition domain in complex with benzimidazole D-galactal ligand== | ||
<StructureSection load='7p1m' size='340' side='right'caption='[[7p1m]]' scene=''> | <StructureSection load='7p1m' size='340' side='right'caption='[[7p1m]], [[Resolution|resolution]] 1.52Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7P1M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7P1M FirstGlance]. <br> | <table><tr><td colspan='2'>[[7p1m]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7P1M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7P1M FirstGlance]. <br> | ||
</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=7p1m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7p1m OCA], [https://pdbe.org/7p1m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7p1m RCSB], [https://www.ebi.ac.uk/pdbsum/7p1m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7p1m ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4IU:2-[[(2R,3R,4R)-2-(hydroxymethyl)-3-oxidanyl-3,4-dihydro-2H-pyran-4-yl]oxymethyl]-3-methyl-benzimidazole-5-carboxylic+acid'>4IU</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=7p1m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7p1m OCA], [https://pdbe.org/7p1m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7p1m RCSB], [https://www.ebi.ac.uk/pdbsum/7p1m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7p1m ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/LEG8_HUMAN LEG8_HUMAN]] Lectin with a marked preference for 3'-O-sialylated and 3'-O-sulfated glycans.<ref>PMID:21288902</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Galectin-8 is a carbohydrate-binding protein that plays a crucial role in tumor progression and metastasis, antibacterial autophagy, modulation of the immune system, and bone remodeling. The design, synthesis, and protein affinity evaluation of a set of C-3 substituted benzimidazole and quinoline d-galactal derivatives identified a d-galactal-benzimidazole hybrid as a selective ligand for the galectin-8 N-terminal domain (galectin-8N), with a K d of 48 muM and 15-fold selectivity over galectin-3 and even better selectivity over the other mammalian galectins. X-ray structural analysis of galectin-8N in complex with one benzimidazole- and one quinoline-galactal derivative at 1.52 and 2.1 A together with molecular dynamics simulations and quantum mechanical calculations of galectin-8N in complex with the benzimidazole derivative revealed orbital overlap between a NH LUMO of Arg45 with electron rich HOMOs of the olefin and O4 of the d-galactal. Such overlap is hypothesized to contribute to the high affinity of the d-galactal-derived ligands for galectin-8N. A (3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay evaluation of the d-galactal-benzimidazole hybrid and an analogous galactoside derivative on a panel of cell lines with MTS assay showed no effect on cell viability up to 100 muM concentration. A subsequent functional assay using the MDA-MB-231 cell line demonstrated that the d-galactal-benzimidazole hybrid and the analogous galactoside derivative reduced the secretion of the proinflammatory cytokines interleukin-6 (IL-6) and IL-8 in a dose-dependent manner. Therefore, these compounds represent potential probes for galectin-8N pharmacology investigations and possibly promising leads for the design and synthesis of potent and selective galectin-8 inhibitors as potential antitumor and anti-inflammatory agents. | |||
Structure-Guided Design of d-Galactal Derivatives with High Affinity and Selectivity for the Galectin-8 N-Terminal Domain.,Hassan M, Baussiere F, Guzelj S, Sundin AP, Hakansson M, Kovacic R, Leffler H, Tomasic T, Anderluh M, Jakopin Z, Nilsson UJ ACS Med Chem Lett. 2021 Nov 2;12(11):1745-1752. doi:, 10.1021/acsmedchemlett.1c00371. eCollection 2021 Nov 11. PMID:34795863<ref>PMID:34795863</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7p1m" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Hakansson M]] | [[Category: Hakansson, M]] | ||
[[Category: Hassan M]] | [[Category: Hassan, M]] | ||
[[Category: Kovacic R]] | [[Category: Kovacic, R]] | ||
[[Category: Nilsson | [[Category: Nilsson, J U]] | ||
[[Category: Complex]] | |||
[[Category: D-galactal]] | |||
[[Category: Galectin]] | |||
[[Category: Inhibitor]] | |||
[[Category: Lectin]] | |||
[[Category: Sugar binding protein]] | |||
