2g7c

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{{Seed}}
 
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[[Image:2g7c.png|left|200px]]
 
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==Clostridium difficile Toxin A Fragment Bound to aGal(1,3)bGal(1,4)bGlcNAc==
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The line below this paragraph, containing "STRUCTURE_2g7c", creates the "Structure Box" on the page.
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<StructureSection load='2g7c' size='340' side='right'caption='[[2g7c]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[2g7c]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Clostridioides_difficile Clostridioides difficile]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2G7C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2G7C FirstGlance]. <br>
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</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&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GAL:BETA-D-GALACTOSE'>GAL</scene>, <scene name='pdbligand=GLA:ALPHA+D-GALACTOSE'>GLA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
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{{STRUCTURE_2g7c| PDB=2g7c | SCENE= }}
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2g7c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2g7c OCA], [https://pdbe.org/2g7c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2g7c RCSB], [https://www.ebi.ac.uk/pdbsum/2g7c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2g7c ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/TCDA_CLODI TCDA_CLODI] Precursor of a cytotoxin that targets and disrupts the colonic epithelium, inducing the host inflammatory and innate immune responses and resulting in diarrhea and pseudomembranous colitis (PubMed:20844489). TcdA and TcdB constitute the main toxins that mediate the pathology of C.difficile infection, an opportunistic pathogen that colonizes the colon when the normal gut microbiome is disrupted (PubMed:19252482, PubMed:20844489). Compared to TcdB, TcdA is less virulent and less important for inducing the host inflammatory and innate immune responses (PubMed:19252482). This form constitutes the precursor of the toxin: it enters into host cells and mediates autoprocessing to release the active toxin (Glucosyltransferase TcdA) into the host cytosol (By similarity). Targets colonic epithelia by binding to some receptor, and enters host cells via clathrin-mediated endocytosis (By similarity). Binding to LDLR, as well as carbohydrates and sulfated glycosaminoglycans on host cell surface contribute to entry into cells (PubMed:1670930, PubMed:31160825, PubMed:16622409). In contrast to TcdB, Frizzled receptors FZD1, FZD2 and FZD7 do not act as host receptors in the colonic epithelium for TcdA (PubMed:27680706). Once entered into host cells, acidification in the endosome promotes the membrane insertion of the translocation region and formation of a pore, leading to translocation of the GT44 and peptidase C80 domains across the endosomal membrane (By similarity). This activates the peptidase C80 domain and autocatalytic processing, releasing the N-terminal part (Glucosyltransferase TcdA), which constitutes the active part of the toxin, in the cytosol (PubMed:17334356, PubMed:19553670, PubMed:27571750).[UniProtKB:P18177]<ref>PMID:16622409</ref> <ref>PMID:1670930</ref> <ref>PMID:17334356</ref> <ref>PMID:19252482</ref> <ref>PMID:19553670</ref> <ref>PMID:20844489</ref> <ref>PMID:27571750</ref> <ref>PMID:27680706</ref> <ref>PMID:31160825</ref> Active form of the toxin, which is released into the host cytosol following autoprocessing and inactivates small GTPases (PubMed:7775453, PubMed:24905543, PubMed:30622517, PubMed:22747490, PubMed:22267739). Acts by mediating monoglucosylation of small GTPases of the Rho family (Rac1, RhoA, RhoB, RhoC, Rap2A and Cdc42) in host cells at the conserved threonine residue located in the switch I region ('Thr-37/35'), using UDP-alpha-D-glucose as the sugar donor (PubMed:7775453, PubMed:24905543, PubMed:30622517, PubMed:22747490, PubMed:22267739). Monoglucosylation of host small GTPases completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption and cell death, resulting in the loss of colonic epithelial barrier function (PubMed:7775453). Also able to catalyze monoglucosylation of some members of the Ras family (H-Ras/HRAS, K-Ras/KRAS and N-Ras/NRAS), but with much less efficiency than with Rho proteins, suggesting that it does not act on Ras proteins in vivo (PubMed:30622517).<ref>PMID:22267739</ref> <ref>PMID:22747490</ref> <ref>PMID:24905543</ref> <ref>PMID:30622517</ref> <ref>PMID:7775453</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/g7/2g7c_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=2g7c ConSurf].
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<div style="clear:both"></div>
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== Publication Abstract from PubMed ==
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Clostridium difficile TcdA is a large toxin that binds carbohydrates on intestinal epithelial cells. A 2-A resolution cocrystal structure reveals two molecules of alpha-Gal-(1,3)-beta-Gal-(1,4)-beta-GlcNAcO(CH(2))(8)CO(2)CH(3) binding in an extended conformation to TcdA. Residues forming key contacts with the trisaccharides are conserved in all seven putative binding sites in TcdA, suggesting a mode of multivalent binding that may be exploited for the rational design of novel therapeutics.
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===Clostridium difficile Toxin A Fragment Bound to aGal(1,3)bGal(1,4)bGlcNAc===
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Carbohydrate recognition by Clostridium difficile toxin A.,Greco A, Ho JG, Lin SJ, Palcic MM, Rupnik M, Ng KK Nat Struct Mol Biol. 2006 May;13(5):460-1. Epub 2006 Apr 16. PMID:16622409<ref>PMID:16622409</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 2g7c" style="background-color:#fffaf0;"></div>
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(as it appears on PubMed at http://www.pubmed.gov), where 16622409 is the PubMed ID number.
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== References ==
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<references/>
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{{ABSTRACT_PUBMED_16622409}}
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__TOC__
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</StructureSection>
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==About this Structure==
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[[Category: Clostridioides difficile]]
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2G7C is a 2 chains structure of sequences from [http://en.wikipedia.org/wiki/Clostridium_difficile Clostridium difficile]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2G7C OCA].
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[[Category: Large Structures]]
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[[Category: Greco A]]
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==Reference==
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[[Category: Ho JGS]]
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<ref group="xtra">PMID:16622409</ref><references group="xtra"/>
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[[Category: Lin SJ]]
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[[Category: Clostridium difficile]]
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[[Category: Ng KKS]]
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[[Category: Greco, A.]]
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[[Category: Palcic MM]]
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[[Category: Ho, J G.S.]]
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[[Category: Rupnik M]]
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[[Category: Lin, S J.]]
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[[Category: Ng, K K.S.]]
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[[Category: Palcic, M M.]]
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[[Category: Rupnik, M.]]
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[[Category: Bacterial toxin]]
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[[Category: Linear b trisaccharide]]
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[[Category: Protein-carbohydrate complex]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Feb 17 09:09:21 2009''
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Current revision

Clostridium difficile Toxin A Fragment Bound to aGal(1,3)bGal(1,4)bGlcNAc

PDB ID 2g7c

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