7tdm: Difference between revisions
New page: '''Unreleased structure''' The entry 7tdm is ON HOLD until Jan 29 2023 Authors: Vecchio, A.J. Description: CryoEM Structure of sFab COP-2 Complex with human claudin-4 and Clostridium p... |
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==CryoEM Structure of sFab COP-2 Complex with human claudin-4 and Clostridium perfringens enterotoxin C-terminal domain== | |||
<StructureSection load='7tdm' size='340' side='right'caption='[[7tdm]], [[Resolution|resolution]] 6.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7tdm]] 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=7TDM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TDM 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]] 6.9Å</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=7tdm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tdm OCA], [https://pdbe.org/7tdm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tdm RCSB], [https://www.ebi.ac.uk/pdbsum/7tdm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tdm ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/CLD4_HUMAN CLD4_HUMAN] CLDN4 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CLD4_HUMAN CLD4_HUMAN] Channel-forming tight junction protein that mediates paracellular chloride transport in the kidney. Plays a critical role in the paracellular reabsorption of filtered chloride in the kidney collecting ducts. Claudins play a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity.[UniProtKB:O35054] | |||
<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. | |||
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 Sep;298(9):102357. doi: 10.1016/j.jbc.2022.102357. Epub 2022 , Aug 9. PMID:35952760<ref>PMID:35952760</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Vecchio | <div class="pdbe-citations 7tdm" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Antibody 3D structures|Antibody 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Clostridium perfringens]] | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Vecchio AJ]] | |||