7ujj: Difference between revisions
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The | ==Stx2a and DARPin complex== | ||
<StructureSection load='7ujj' size='340' side='right'caption='[[7ujj]], [[Resolution|resolution]] 6.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7ujj]] is a 7 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_phage_933W Escherichia phage 933W] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7UJJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UJJ FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PS:3-PYRIDINIUM-1-YLPROPANE-1-SULFONATE'>1PS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=7ujj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ujj OCA], [https://pdbe.org/7ujj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ujj RCSB], [https://www.ebi.ac.uk/pdbsum/7ujj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ujj ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/STXA_BP933 STXA_BP933] The A subunit is responsible for inhibiting protein synthesis through the catalytic inactivation of 60S ribosomal subunits. After endocytosis, the A subunit is cleaved by furin in two fragments, A1 and A2: A1 is the catalytically active fragment, and A2 is essential for holotoxin assembly with the B subunits. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Shiga toxin-producing E. coli (STEC) is a common cause of bloody diarrhea. The pathology of STEC infection derives from two exotoxins-Shiga toxin 1 (Stx1) and Shiga toxin 2 (Stx2)-that are secreted by STEC in the gut, from where they are systemically absorbed, causing severe kidney damage leading to hemolytic uremic syndrome (HUS). Currently, there is no effective treatment for HUS, and only supportive care is recommended. We report the engineering of a panel of designed ankyrin repeat proteins (DARPin) with potent neutralization activity against Stx2a, the major subtype associated with HUS. The best dimeric DARPin, SD5, created via a combination of directed evolution and rational design, neutralizes Stx2a with a half maximal effective concentration (EC(50)) of 0.61 nM in vitro. The two monomeric DARPin constituents of SD5 exhibit complementary functions-SHT targets the enzymatic A subunit of Stx2a and inhibits the toxin's catalytic activity, while DARPin #3 binds the B subunit, based on the cryo-EM study, and induces a novel conformational change in the B subunit that distorts its five-fold symmetry and presumably interferes with toxin attachment to target cells. SD5 was fused to an albumin-binding DARPin, and the resulting trimeric DARPin DA1-SD5 efficiently protects mice in a toxin challenge model, pointing to a high potential of this DARPin as a therapeutic for STEC infection. Finally, the unprecedented toxin conformational change induced by DARPin #3 represents a novel mode of action for neutralizing Stx2 toxicity and reveals new targets for future drug development. | |||
A Multi-Specific DARPin Potently Neutralizes Shiga Toxin 2 via Simultaneous Modulation of Both Toxin Subunits.,Zeng Y, Jiang M, Robinson S, Peng Z, Chonira V, Simeon R, Tzipori S, Zhang J, Chen Z Bioengineering (Basel). 2022 Sep 27;9(10):511. doi: , 10.3390/bioengineering9100511. PMID:36290479<ref>PMID:36290479</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 7ujj" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Escherichia phage 933W]] | |||
[[Category: Large Structures]] | |||
[[Category: Synthetic construct]] | |||
[[Category: Jiang M]] | |||
[[Category: Zhang J]] | |||