View source for 2vl8


==CRYSTAL STRUCTURE OF THE CATALYTIC DOMAIN OF LETHAL TOXIN FROM CLOSTRIDIUM SORDELLII IN COMPLEX WITH UDP, CASTANOSPERMINE AND CALCIUM ION==
<StructureSection load='2vl8' size='340' side='right'caption='[[2vl8]], [[Resolution|resolution]] 2.31&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2vl8]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Paeniclostridium_sordellii Paeniclostridium sordellii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VL8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VL8 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]] 2.31&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CTS:CASTANOSPERMINE'>CTS</scene>, <scene name='pdbligand=UDP:URIDINE-5-DIPHOSPHATE'>UDP</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=2vl8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vl8 OCA], [https://pdbe.org/2vl8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vl8 RCSB], [https://www.ebi.ac.uk/pdbsum/2vl8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vl8 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/TCSL1_PAESO TCSL1_PAESO] Precursor of a cytotoxin that targets the vascular endothelium, inducing an anti-inflammatory effect and resulting in lethal toxic shock syndrome (PubMed:19527792, PubMed:24919149, PubMed:29146177). TcsL constitutes the main toxin that mediates the pathology of P.sordellii infection, an anaerobic Gram-positive bacterium found in soil and in the gastrointestinal and vaginal tracts of animals and humans; although the majority of carriers are asymptomatic, pathogenic P.sordellii infections arise rapidly and are highly lethal (PubMed:29146177). This form constitutes the precursor of the toxin: it enters into host cells and mediates autoprocessing to release the active toxin (Glucosyltransferase TcsL) into the host cytosol (PubMed:32302524, PubMed:17334356, PubMed:27303685). Targets vascular endothelium by binding to the semaphorin proteins SEMA6A and SEMA6B, and enters host cells via clathrin-mediated endocytosis (PubMed:32302524). 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 TcsL), which constitutes the active part of the toxin, in the cytosol (PubMed:17334356, PubMed:27303685).[UniProtKB:P18177]<ref>PMID:17334356</ref> <ref>PMID:19527792</ref> <ref>PMID:24919149</ref> <ref>PMID:27303685</ref> <ref>PMID:32302524</ref> <ref>PMID:29146177</ref>   Active form of the toxin, which is released into the host cytosol following autoprocessing and inactivates small GTPases (PubMed:8626575, PubMed:8626586, PubMed:9632667, PubMed:17901056, PubMed:19744486, PubMed:24905543, PubMed:24919149, PubMed:27303685, PubMed:27023605, PubMed:30622517). Acts by mediating monoglucosylation of small GTPases of the Ras (H-Ras/HRAS, K-Ras/KRAS, N-Ras/NRAS and Ral/RALA) family 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:8858106, PubMed:8626575, PubMed:8626586, PubMed:9632667, PubMed:17901056, PubMed:19744486, PubMed:24905543, PubMed:24919149, PubMed:27023605, PubMed:30622517). Also able to catalyze monoglucosylation of some members of the Rho family (Rac1 and Rap2A), but with less efficiency than with Ras proteins (PubMed:8626586, PubMed:9632667, PubMed:19744486, PubMed:24905543). Monoglucosylation of host small GTPases completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form and leading to apoptosis (PubMed:8626586, PubMed:9632667, PubMed:17910886). Induces an anti-inflammatory effect, mainly by inactivating Ras proteins which results in blockage of the cell cycle and killing of immune cells (PubMed:17910886, PubMed:24919149). The absence or moderate local inflammatory response allows C.sordellii spreading in deep tissues, production of toxin which is released in the general circulation and causes a toxic shock syndrome (PubMed:24919149, PubMed:29146177).<ref>PMID:17901056</ref> <ref>PMID:17910886</ref> <ref>PMID:19744486</ref> <ref>PMID:24905543</ref> <ref>PMID:24919149</ref> <ref>PMID:27023605</ref> <ref>PMID:27303685</ref> <ref>PMID:30622517</ref> <ref>PMID:8626575</ref> <ref>PMID:8626586</ref> <ref>PMID:8858106</ref> <ref>PMID:9632667</ref> <ref>PMID:29146177</ref> 
== 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/vl/2vl8_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=2vl8 ConSurf].
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== Publication Abstract from PubMed ==
Castanospermine was identified as an inhibitor of the Rho/Ras-glucosylating Clostridium sordellii lethal toxin and Clostridium difficile toxin B. Microinjection of castanospermine into embryonic bovine lung cells prevented the cytotoxic effects of toxins. The crystal structure of the glucosyltransferase domain of C. sordellii lethal toxin in complex with castanospermine, UDP and a calcium ion was solved at a resolution of 2.3A. The inhibitor binds in a conformation that brings its four hydroxyl groups and its N-atom almost exactly in the positions of the four hydroxyls and of the ring oxygen of the glucosyl moiety of UDP-glucose, respectively.

Inhibition of the glucosyltransferase activity of clostridial Rho/Ras-glucosylating toxins by castanospermine.,Jank T, Ziegler MO, Schulz GE, Aktories K FEBS Lett. 2008 Jun 25;582(15):2277-82. Epub 2008 May 27. PMID:18505687<ref>PMID:18505687</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Paeniclostridium sordellii]]
[[Category: Aktories K]]
[[Category: Jank T]]
[[Category: Schulz GE]]
[[Category: Ziegler MOP]]