7tdn
From Proteopedia
(Difference between revisions)
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==CryoEM Structure of sFab COP-3 Complex with human claudin-4 and Clostridium perfringens enterotoxin C-terminal domain== | ==CryoEM Structure of sFab COP-3 Complex with human claudin-4 and Clostridium perfringens enterotoxin C-terminal domain== | ||
| - | <StructureSection load='7tdn' size='340' side='right'caption='[[7tdn]]' scene=''> | + | <StructureSection load='7tdn' size='340' side='right'caption='[[7tdn]], [[Resolution|resolution]] 5.00Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TDN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TDN FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7tdn]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Clostridium_perfringens Clostridium perfringens] 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=7TDN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TDN FirstGlance]. <br> |
</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=7tdn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tdn OCA], [https://pdbe.org/7tdn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tdn RCSB], [https://www.ebi.ac.uk/pdbsum/7tdn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tdn ProSAT]</span></td></tr> | </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=7tdn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tdn OCA], [https://pdbe.org/7tdn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tdn RCSB], [https://www.ebi.ac.uk/pdbsum/7tdn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tdn ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [[https://www.uniprot.org/uniprot/ELTB_CLOPF ELTB_CLOPF]] This enterotoxin is responsible for many cases of a mild type of food poisoning. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Strains of Clostridium perfringens produce a two-domain enterotoxin (CpE) that afflicts humans and domesticated animals, causing prevalent gastrointestinal illnesses. CpE's C-terminal domain (cCpE) binds cell surface receptors, followed by a restructuring of its N-terminal domain to form a membrane-penetrating beta-barrel pore, which is toxic to epithelial cells of the gut. The claudin family of membrane proteins are known receptors for CpE and also control the architecture and function of cell-cell contacts (tight junctions) that create barriers to intercellular molecular transport. CpE binding and assembly disables claudin barrier function and induces cytotoxicity via beta-pore formation, disrupting gut homeostasis; however, a structural basis of this process and strategies to inhibit the claudin-CpE interactions that trigger it are both lacking. Here, we used a synthetic antigen-binding fragment (sFab) library to discover two sFabs that bind claudin-4 and cCpE complexes. We established these sFabs' mode of molecular recognition and binding properties and determined structures of each sFab bound to claudin-4/cCpE complexes using cryo-EM. The structures reveal that the sFabs bind a shared epitope, but conform distinctly, which explains their unique binding equilibria. Mutagenesis of antigen/sFab interfaces observed therein result in binding changes, validating the structures, and uncovering the sFab's targeting mechanism. From these insights, we generated a model for CpE's claudin-bound beta-pore that predicted sFabs would not prevent cytotoxicity, which we then verified in vivo. Taken together, this work demonstrates the development and mechanism of claudin/cCpE-binding sFabs that provide a framework and strategy for obstructing claudin/CpE assembly to treat CpE-linked gastrointestinal diseases. | ||
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| + | Development, structure, and mechanism of synthetic antibodies that target claudin and Clostridium perfringens enterotoxin complexes.,Orlando BJ, Dominik PK, Roy S, Ogbu CP, Erramilli SK, Kossiakoff AA, Vecchio AJ J Biol Chem. 2022 Aug 8:102357. doi: 10.1016/j.jbc.2022.102357. PMID:35952760<ref>PMID:35952760</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7tdn" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Clostridium perfringens]] | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Vecchio AJ]] | [[Category: Vecchio AJ]] | ||
Revision as of 07:54, 21 September 2022
CryoEM Structure of sFab COP-3 Complex with human claudin-4 and Clostridium perfringens enterotoxin C-terminal domain
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