2x52: Difference between revisions
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< | ==CRYSTAL STRUCTURE OF WHEAT GERM AGGLUTININ ISOLECTIN 3 IN COMPLEX WITH A SYNTHETIC DIVALENT CARBOHYDRATE LIGAND== | ||
<StructureSection load='2x52' size='340' side='right'caption='[[2x52]], [[Resolution|resolution]] 1.70Å' scene=''> | |||
You may | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2x52]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Triticum_aestivum Triticum aestivum]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=2uwz 2uwz]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2X52 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2X52 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]] 1.7Å</td></tr> | |||
-- | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=GYT:BIS-(2-ACETAMIDO-2-DEOXY-ALPHA-D-GLUCOPYRANOSYLOXYCARBONYL)-4,7,10-TRIOXA-1,13-TRIDECANEDIAMINE'>GYT</scene>, <scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</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=2x52 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2x52 OCA], [https://pdbe.org/2x52 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2x52 RCSB], [https://www.ebi.ac.uk/pdbsum/2x52 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2x52 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/AGI3_WHEAT AGI3_WHEAT] N-acetyl-D-glucosamine / N-acetyl-D-neuraminic acid binding lectin. | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/x5/2x52_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2x52 ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The inhibition of carbohydrate-protein interactions by tailored multivalent ligands is a powerful strategy for the treatment of many human diseases. Crucial for the success of this approach is an understanding of the molecular mechanisms as to how a binding enhancement of a multivalent ligand is achieved. We have synthesized a series of multivalent N-acetylglucosamine (GlcNAc) derivatives and studied their interaction with the plant lectin wheat germ agglutinin (WGA) by an enzyme-linked lectin assay (ELLA) and X-ray crystallography. The solution conformation of one ligand was determined by NMR spectroscopy. Employing a GlcNAc carbamate motif with alpha-configuration and by systematic variation of the spacer length, we were able to identify divalent ligands with unprecedented high WGA binding potency. The best divalent ligand has an IC(50) value of 9.8 muM (ELLA) corresponding to a relative potency of 2350 (1170 on a valency-corrected basis, i.e., per mol sugar contained) compared to free GlcNAc. X-ray crystallography of the complex of WGA and the second best, closely related divalent ligand explains this activity. Four divalent molecules simultaneously bind to WGA with each ligand bridging adjacent binding sites. This shows for the first time that all eight sugar binding sites of the WGA dimer are simultaneously functional. We also report a tetravalent neoglycopeptide with an IC(50) value of 0.9 muM being 25 500 times higher than that of GlcNAc (6400 times per contained sugar) and the X-ray structure analysis of its complex with glutaraldehyde-cross-linked WGA. Comparison of the crystal structure and the solution NMR structure of the neoglycopeptide as well as results from the ELLA suggest that the conformation of the glycopeptide in solution is already preorganized in a way supporting multivalent binding to the protein. Our findings show that bridging adjacent protein binding sites by multivalent ligands is a valid strategy to find high-affinity protein ligands and that even subtle changes of the linker structure can have a significant impact on the binding affinity. | |||
Structural Basis of Multivalent Binding to Wheat Germ Agglutinin.,Schwefel D, Maierhofer C, Beck JG, Seeberger S, Diederichs K, Moller HM, Welte W, Wittmann V J Am Chem Soc. 2010 Jun 7. PMID:20527753<ref>PMID:20527753</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2x52" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Agglutinin 3D structures|Agglutinin 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | [[Category: Large Structures]] | ||
== | |||
< | |||
[[Category: Triticum aestivum]] | [[Category: Triticum aestivum]] | ||
[[Category: Diederichs | [[Category: Diederichs K]] | ||
[[Category: Maierhofer | [[Category: Maierhofer C]] | ||
[[Category: Schwefel | [[Category: Schwefel D]] | ||
[[Category: Welte | [[Category: Welte W]] | ||
[[Category: Wittmann | [[Category: Wittmann V]] | ||
Latest revision as of 13:23, 20 December 2023
CRYSTAL STRUCTURE OF WHEAT GERM AGGLUTININ ISOLECTIN 3 IN COMPLEX WITH A SYNTHETIC DIVALENT CARBOHYDRATE LIGANDCRYSTAL STRUCTURE OF WHEAT GERM AGGLUTININ ISOLECTIN 3 IN COMPLEX WITH A SYNTHETIC DIVALENT CARBOHYDRATE LIGAND
Structural highlights
FunctionAGI3_WHEAT N-acetyl-D-glucosamine / N-acetyl-D-neuraminic acid binding lectin. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe inhibition of carbohydrate-protein interactions by tailored multivalent ligands is a powerful strategy for the treatment of many human diseases. Crucial for the success of this approach is an understanding of the molecular mechanisms as to how a binding enhancement of a multivalent ligand is achieved. We have synthesized a series of multivalent N-acetylglucosamine (GlcNAc) derivatives and studied their interaction with the plant lectin wheat germ agglutinin (WGA) by an enzyme-linked lectin assay (ELLA) and X-ray crystallography. The solution conformation of one ligand was determined by NMR spectroscopy. Employing a GlcNAc carbamate motif with alpha-configuration and by systematic variation of the spacer length, we were able to identify divalent ligands with unprecedented high WGA binding potency. The best divalent ligand has an IC(50) value of 9.8 muM (ELLA) corresponding to a relative potency of 2350 (1170 on a valency-corrected basis, i.e., per mol sugar contained) compared to free GlcNAc. X-ray crystallography of the complex of WGA and the second best, closely related divalent ligand explains this activity. Four divalent molecules simultaneously bind to WGA with each ligand bridging adjacent binding sites. This shows for the first time that all eight sugar binding sites of the WGA dimer are simultaneously functional. We also report a tetravalent neoglycopeptide with an IC(50) value of 0.9 muM being 25 500 times higher than that of GlcNAc (6400 times per contained sugar) and the X-ray structure analysis of its complex with glutaraldehyde-cross-linked WGA. Comparison of the crystal structure and the solution NMR structure of the neoglycopeptide as well as results from the ELLA suggest that the conformation of the glycopeptide in solution is already preorganized in a way supporting multivalent binding to the protein. Our findings show that bridging adjacent protein binding sites by multivalent ligands is a valid strategy to find high-affinity protein ligands and that even subtle changes of the linker structure can have a significant impact on the binding affinity. Structural Basis of Multivalent Binding to Wheat Germ Agglutinin.,Schwefel D, Maierhofer C, Beck JG, Seeberger S, Diederichs K, Moller HM, Welte W, Wittmann V J Am Chem Soc. 2010 Jun 7. PMID:20527753[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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