6oq8

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<StructureSection load='6oq8' size='340' side='right'caption='[[6oq8]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
<StructureSection load='6oq8' size='340' side='right'caption='[[6oq8]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6oq8]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_difficilis"_hall_and_o'toole_1935 "bacillus difficilis" hall and o'toole 1935] and [http://en.wikipedia.org/wiki/Camelidae Camelidae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OQ8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6OQ8 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6oq8]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Camelidae Camelidae] and [https://en.wikipedia.org/wiki/Clostridioides_difficile Clostridioides difficile]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OQ8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OQ8 FirstGlance]. <br>
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</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">toxB, tcdB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1496 "Bacillus difficilis" Hall and O'Toole 1935])</td></tr>
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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]] 2.2&#8491;</td></tr>
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<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=6oq8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6oq8 OCA], [http://pdbe.org/6oq8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6oq8 RCSB], [http://www.ebi.ac.uk/pdbsum/6oq8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6oq8 ProSAT]</span></td></tr>
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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=6oq8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6oq8 OCA], [https://pdbe.org/6oq8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6oq8 RCSB], [https://www.ebi.ac.uk/pdbsum/6oq8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6oq8 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/TOXB_CLODI TOXB_CLODI]] Cytotoxin.
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[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:8144660, PubMed:7777059, PubMed:16157585, PubMed:17901056, PubMed:24905543, PubMed:24919149). 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:7777059, PubMed:16157585, PubMed:17901056, PubMed:24905543, PubMed:24919149). 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:7777059, PubMed:24919149).<ref>PMID:16157585</ref> <ref>PMID:17901056</ref> <ref>PMID:24905543</ref> <ref>PMID:24919149</ref> <ref>PMID:7777059</ref> <ref>PMID:8144660</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Clostridium difficile is an opportunistic pathogen that establishes in the colon when the gut microbiota are disrupted by antibiotics or disease. C. difficile infection (CDI) is largely caused by two virulence factors, TcdA and TcdB. Here, we report a 3.87-A-resolution crystal structure of TcdB holotoxin that captures a unique conformation of TcdB at endosomal pH. Complementary biophysical studies suggest that the C-terminal combined repetitive oligopeptides (CROPs) domain of TcdB is dynamic and can sample open and closed conformations that may facilitate modulation of TcdB activity in response to environmental and cellular cues during intoxication. Furthermore, we report three crystal structures of TcdB-antibody complexes that reveal how antibodies could specifically inhibit the activities of individual TcdB domains. Our studies provide novel insight into the structure and function of TcdB holotoxin and identify intrinsic vulnerabilities that could be exploited to develop new therapeutics and vaccines for the treatment of CDI.
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Structure of the full-length Clostridium difficile toxin B.,Chen P, Lam KH, Liu Z, Mindlin FA, Chen B, Gutierrez CB, Huang L, Zhang Y, Hamza T, Feng H, Matsui T, Bowen ME, Perry K, Jin R Nat Struct Mol Biol. 2019 Jul 15. pii: 10.1038/s41594-019-0268-0. doi:, 10.1038/s41594-019-0268-0. PMID:31308519<ref>PMID:31308519</ref>
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==See Also==
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*[[Antibody 3D structures|Antibody 3D structures]]
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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>
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<div class="pdbe-citations 6oq8" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Bacillus difficilis hall and o'toole 1935]]
 
[[Category: Camelidae]]
[[Category: Camelidae]]
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[[Category: Clostridioides difficile]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Chen, P]]
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[[Category: Chen P]]
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[[Category: Jin, R]]
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[[Category: Jin R]]
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[[Category: Lam, K]]
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[[Category: Lam K]]
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[[Category: Toxin]]
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[[Category: Toxin vhh]]
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Current revision

Structure of the GTD domain of Clostridium difficile toxin B in complex with VHH 7F

PDB ID 6oq8

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