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==Shiga-Like Toxin I B Subunit Complexed with the Bridged-Starfish Inhibitor== | |||
<StructureSection load='1qnu' size='340' side='right'caption='[[1qnu]], [[Resolution|resolution]] 2.23Å' scene=''> | |||
| | == Structural highlights == | ||
<table><tr><td colspan='2'>[[1qnu]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_O157:H7 Escherichia coli O157:H7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1QNU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1QNU 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]] 2.23Å</td></tr> | |||
| | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EMB:METHYL-CARBAMIC+ACID+ETHYL+ESTER'>EMB</scene>, <scene name='pdbligand=GAL:BETA-D-GALACTOSE'>GAL</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=MEC:ETHYL-CARBAMIC+ACID+METHYL+ESTER'>MEC</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=1qnu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1qnu OCA], [https://pdbe.org/1qnu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1qnu RCSB], [https://www.ebi.ac.uk/pdbsum/1qnu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1qnu ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/V5URS0_9CAUD V5URS0_9CAUD] The B subunit is responsible for the binding of the holotoxin to specific receptors on the target cell surface, such as globotriaosylceramide (Gb3) in human intestinal microvilli.[ARBA:ARBA00003218] | |||
== 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/qn/1qnu_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=1qnu ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The diseases caused by Shiga and cholera toxins account for the loss of millions of lives each year. Both belong to the clinically significant subset of bacterial AB5 toxins consisting of an enzymatically active A subunit that gains entry to susceptible mammalian cells after oligosaccharide recognition by the B5 homopentamer. Therapies might target the obligatory oligosaccharide-toxin recognition event, but the low intrinsic affinity of carbohydrate-protein interactions hampers the development of low-molecular-weight inhibitors. The toxins circumvent low affinity by binding simultaneously to five or more cell-surface carbohydrates. Here we demonstrate the use of the crystal structure of the B5 subunit of Escherichia coli O157:H7 Shiga-like toxin I (SLT-I) in complex with an analogue of its carbohydrate receptor to design an oligovalent, water-soluble carbohydrate ligand (named STARFISH), with subnanomolar inhibitory activity. The in vitro inhibitory activity is 1-10-million-fold higher than that of univalent ligands and is by far the highest molar activity of any inhibitor yet reported for Shiga-like toxins I and II. Crystallography of the STARFISH/Shiga-like toxin I complex explains this activity. Two trisaccharide receptors at the tips of each of five spacer arms simultaneously engage all five B subunits of two toxin molecules. | The diseases caused by Shiga and cholera toxins account for the loss of millions of lives each year. Both belong to the clinically significant subset of bacterial AB5 toxins consisting of an enzymatically active A subunit that gains entry to susceptible mammalian cells after oligosaccharide recognition by the B5 homopentamer. Therapies might target the obligatory oligosaccharide-toxin recognition event, but the low intrinsic affinity of carbohydrate-protein interactions hampers the development of low-molecular-weight inhibitors. The toxins circumvent low affinity by binding simultaneously to five or more cell-surface carbohydrates. Here we demonstrate the use of the crystal structure of the B5 subunit of Escherichia coli O157:H7 Shiga-like toxin I (SLT-I) in complex with an analogue of its carbohydrate receptor to design an oligovalent, water-soluble carbohydrate ligand (named STARFISH), with subnanomolar inhibitory activity. The in vitro inhibitory activity is 1-10-million-fold higher than that of univalent ligands and is by far the highest molar activity of any inhibitor yet reported for Shiga-like toxins I and II. Crystallography of the STARFISH/Shiga-like toxin I complex explains this activity. Two trisaccharide receptors at the tips of each of five spacer arms simultaneously engage all five B subunits of two toxin molecules. | ||
Shiga-like toxins are neutralized by tailored multivalent carbohydrate ligands.,Kitov PI, Sadowska JM, Mulvey G, Armstrong GD, Ling H, Pannu NS, Read RJ, Bundle DR Nature. 2000 Feb 10;403(6770):669-72. PMID:10688205<ref>PMID:10688205</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 1qnu" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Shiga toxin 3D structures|Shiga toxin 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Escherichia coli O157:H7]] | |||
[[Category: Large Structures]] | |||
[[Category: Hayakawa K]] | |||
[[Category: Pannu NS]] | |||
[[Category: Read RJ]] | |||
Latest revision as of 11:46, 6 November 2024
Shiga-Like Toxin I B Subunit Complexed with the Bridged-Starfish InhibitorShiga-Like Toxin I B Subunit Complexed with the Bridged-Starfish Inhibitor
Structural highlights
FunctionV5URS0_9CAUD The B subunit is responsible for the binding of the holotoxin to specific receptors on the target cell surface, such as globotriaosylceramide (Gb3) in human intestinal microvilli.[ARBA:ARBA00003218] 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 diseases caused by Shiga and cholera toxins account for the loss of millions of lives each year. Both belong to the clinically significant subset of bacterial AB5 toxins consisting of an enzymatically active A subunit that gains entry to susceptible mammalian cells after oligosaccharide recognition by the B5 homopentamer. Therapies might target the obligatory oligosaccharide-toxin recognition event, but the low intrinsic affinity of carbohydrate-protein interactions hampers the development of low-molecular-weight inhibitors. The toxins circumvent low affinity by binding simultaneously to five or more cell-surface carbohydrates. Here we demonstrate the use of the crystal structure of the B5 subunit of Escherichia coli O157:H7 Shiga-like toxin I (SLT-I) in complex with an analogue of its carbohydrate receptor to design an oligovalent, water-soluble carbohydrate ligand (named STARFISH), with subnanomolar inhibitory activity. The in vitro inhibitory activity is 1-10-million-fold higher than that of univalent ligands and is by far the highest molar activity of any inhibitor yet reported for Shiga-like toxins I and II. Crystallography of the STARFISH/Shiga-like toxin I complex explains this activity. Two trisaccharide receptors at the tips of each of five spacer arms simultaneously engage all five B subunits of two toxin molecules. Shiga-like toxins are neutralized by tailored multivalent carbohydrate ligands.,Kitov PI, Sadowska JM, Mulvey G, Armstrong GD, Ling H, Pannu NS, Read RJ, Bundle DR Nature. 2000 Feb 10;403(6770):669-72. PMID:10688205[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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