8qeo
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==cryo-EM structure complex of Frizzled-7 and Clostridioides difficile toxin B== | |
| + | <StructureSection load='8qeo' size='340' side='right'caption='[[8qeo]], [[Resolution|resolution]] 3.26Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8qeo]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Clostridioides_difficile Clostridioides difficile] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8QEO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8QEO FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.26Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</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=8qeo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8qeo OCA], [https://pdbe.org/8qeo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8qeo RCSB], [https://www.ebi.ac.uk/pdbsum/8qeo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8qeo ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/TCDB_CLODI TCDB_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, PubMed:24919149). TcdB constitutes the main toxin that mediates 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 TcdA, TcdB is more virulent and more important for inducing the host inflammatory and innate immune responses (PubMed:19252482, PubMed:24919149). This form constitutes the precursor of the toxin: it enters into host cells and mediates autoprocessing to release the active toxin (Glucosyltransferase TcdB) into the host cytosol (PubMed:10768933, PubMed:11152463, PubMed:12941936, PubMed:17334356, PubMed:20498856). Targets colonic epithelia by binding to the frizzled receptors FZD1, FZD2 and FZD7, and enters host cells via clathrin-mediated endocytosis (PubMed:27680706). Frizzled receptors constitute the major host receptors in the colonic epithelium, but other receptors, such as CSPG4 or NECTIN3/PVRL3, have been identified (PubMed:25547119, PubMed:26038560, PubMed:27680706). Binding to carbohydrates and sulfated glycosaminoglycans on host cell surface also contribute to entry into cells (By similarity). 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 (PubMed:11152463, PubMed:12941936, PubMed:24567384). This activates the peptidase C80 domain and autocatalytic processing, releasing the N-terminal part (Glucosyltransferase TcdB), which constitutes the active part of the toxin, in the cytosol (PubMed:17334356, PubMed:27571750).[UniProtKB:P16154]<ref>PMID:10768933</ref> <ref>PMID:11152463</ref> <ref>PMID:12941936</ref> <ref>PMID:17334356</ref> <ref>PMID:19252482</ref> <ref>PMID:20498856</ref> <ref>PMID:20844489</ref> <ref>PMID:24567384</ref> <ref>PMID:24919149</ref> <ref>PMID:25547119</ref> <ref>PMID:26038560</ref> <ref>PMID:27571750</ref> <ref>PMID:27680706</ref> Active form of the toxin, which is released into the host cytosol following autoprocessing and inactivates small GTPases (PubMed:16157585, PubMed:17901056, PubMed:24905543, PubMed:24919149, PubMed:7777059, PubMed:8144660). Acts by mediating monoglucosylation of small GTPases of the Rho family (Rac1, RhoA, RhoB, RhoC, RhoG 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:16157585, PubMed:17901056, PubMed:24905543, PubMed:24919149, PubMed:7777059). 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:24919149, PubMed:7777059).<ref>PMID:16157585</ref> <ref>PMID:17901056</ref> <ref>PMID:24905543</ref> <ref>PMID:24919149</ref> <ref>PMID:7777059</ref> <ref>PMID:8144660</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The G protein-coupled receptors of the Frizzled (FZD) family, in particular FZD(1,2,7), are receptors that are exploited by Clostridioides difficile toxin B (TcdB), the major virulence factor responsible for pathogenesis associated with Clostridioides difficile infection. We employ a live-cell assay examining the affinity between full-length FZDs and TcdB. Moreover, we present cryoelectron microscopy structures of TcdB alone and in complex with full-length FZD(7), which reveal that large structural rearrangements of the combined repetitive polypeptide domain are required for interaction with FZDs and other TcdB receptors, constituting a first step for receptor recognition. Furthermore, we show that bezlotoxumab, an FDA-approved monoclonal antibody to treat Clostridioides difficile infection, favors the apo-TcdB structure and thus disrupts binding with FZD(7). The dynamic transition between the two conformations of TcdB also governs the stability of the pore-forming region. Thus, our work provides structural and functional insight into how conformational dynamics of TcdB determine receptor binding. | ||
| - | + | Structural and functional insight into the interaction of Clostridioides difficile toxin B and FZD(7).,Kinsolving J, Bous J, Kozielewicz P, Kosenina S, Shekhani R, Gratz L, Masuyer G, Wang Y, Stenmark P, Dong M, Schulte G Cell Rep. 2024 Feb 27;43(2):113727. doi: 10.1016/j.celrep.2024.113727. Epub 2024 , Feb 2. PMID:38308843<ref>PMID:38308843</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 8qeo" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Clostridioides difficile]] | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Bous J]] | ||
| + | [[Category: Kinsolving J]] | ||
Current revision
cryo-EM structure complex of Frizzled-7 and Clostridioides difficile toxin B
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