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| | ==Galectin-3C in complex with a pair of enantiomeric ligands: S enantiomer== | | ==Galectin-3C in complex with a pair of enantiomeric ligands: S enantiomer== |
| - | <StructureSection load='6qge' size='340' side='right' caption='[[6qge]], [[Resolution|resolution]] 1.16Å' scene=''> | + | <StructureSection load='6qge' size='340' side='right'caption='[[6qge]], [[Resolution|resolution]] 1.16Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6qge]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QGE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6QGE FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6qge]] 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=6QGE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QGE FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=J1E:(2~{S},3~{R},4~{S},5~{R},6~{R})-4-[4-(3-fluorophenyl)-1,2,3-triazol-1-yl]-2-[(2~{S})-3-[4-(3-fluorophenyl)-1,2,3-triazol-1-yl]-2-oxidanyl-propyl]sulfanyl-6-(hydroxymethyl)oxane-3,5-diol'>J1E</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.16Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">LGALS3, MAC2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=J1E:(2~{S},3~{R},4~{S},5~{R},6~{R})-4-[4-(3-fluorophenyl)-1,2,3-triazol-1-yl]-2-[(2~{S})-3-[4-(3-fluorophenyl)-1,2,3-triazol-1-yl]-2-oxidanyl-propyl]sulfanyl-6-(hydroxymethyl)oxane-3,5-diol'>J1E</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6qge FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qge OCA], [http://pdbe.org/6qge PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6qge RCSB], [http://www.ebi.ac.uk/pdbsum/6qge PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6qge ProSAT]</span></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=6qge FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qge OCA], [https://pdbe.org/6qge PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6qge RCSB], [https://www.ebi.ac.uk/pdbsum/6qge PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6qge ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6qge" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6qge" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Galectin 3D structures|Galectin 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Logan, D T]] | + | [[Category: Large Structures]] |
| - | [[Category: Manzoni, F]] | + | [[Category: Logan DT]] |
| - | [[Category: Nilsson, U J]] | + | [[Category: Manzoni F]] |
| - | [[Category: Oksanen, E]] | + | [[Category: Nilsson UJ]] |
| - | [[Category: Verteramo, M L]] | + | [[Category: Oksanen E]] |
| - | [[Category: Cell signalling drug design conformational entropy]]
| + | [[Category: Verteramo ML]] |
| - | [[Category: Sugar binding protein]]
| + | |
| Structural highlights
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
Understanding the driving forces underlying molecular recognition is of fundamental importance in chemistry and biology. The challenge is to unravel the binding thermodynamics into separate contributions and to interpret these in molecular terms. Entropic contributions to the free energy of binding are particularly difficult to assess in this regard. Here we pinpoint the molecular determinants underlying differences in ligand affinity to the carbohydrate recognition domain of galectin-3, using a combination of isothermal titration calorimetry, X-ray crystallography, NMR relaxation, and molecular dynamics simulations followed by conformational entropy and grid inhomogeneous solvation theory (GIST) analyses. Using a pair of diastereomeric ligands that have essentially identical chemical potential in the unbound state, we reduced the problem of dissecting the thermodynamics to a comparison of the two protein-ligand complexes. While the free energies of binding are nearly equal for the R and S diastereomers, greater differences are observed for the enthalpy and entropy, which consequently exhibit compensatory behavior, DeltaDelta H degrees (R - S) = -5 +/- 1 kJ/mol and - TDeltaDelta S degrees (R - S) = 3 +/- 1 kJ/mol. NMR relaxation experiments and molecular dynamics simulations indicate that the protein in complex with the S-stereoisomer has greater conformational entropy than in the R-complex. GIST calculations reveal additional, but smaller, contributions from solvation entropy, again in favor of the S-complex. Thus, conformational entropy apparently dominates over solvation entropy in dictating the difference in the overall entropy of binding. This case highlights an interplay between conformational entropy and solvation entropy, pointing to both opportunities and challenges in drug design.
Interplay between Conformational Entropy and Solvation Entropy in Protein-Ligand Binding.,Verteramo ML, Stenstrom O, Ignjatovic MM, Caldararu O, Olsson MA, Manzoni F, Leffler H, Oksanen E, Logan DT, Nilsson UJ, Ryde U, Akke M J Am Chem Soc. 2019 Feb 6;141(5):2012-2026. doi: 10.1021/jacs.8b11099. Epub 2019 , Jan 23. PMID:30618244[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ 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
- ↑ Verteramo ML, Stenstrom O, Ignjatovic MM, Caldararu O, Olsson MA, Manzoni F, Leffler H, Oksanen E, Logan DT, Nilsson UJ, Ryde U, Akke M. Interplay between Conformational Entropy and Solvation Entropy in Protein-Ligand Binding. J Am Chem Soc. 2019 Feb 6;141(5):2012-2026. doi: 10.1021/jacs.8b11099. Epub 2019 , Jan 23. PMID:30618244 doi:http://dx.doi.org/10.1021/jacs.8b11099
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