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==Pertussis toxin S1 bound to NAD+== | ==Pertussis toxin S1 bound to NAD+== | ||
<StructureSection load='7sky' size='340' side='right'caption='[[7sky]]' scene=''> | <StructureSection load='7sky' size='340' side='right'caption='[[7sky]], [[Resolution|resolution]] 1.37Å' 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=7SKY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SKY FirstGlance]. <br> | <table><tr><td colspan='2'>[[7sky]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7SKY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SKY 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=7sky FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7sky OCA], [https://pdbe.org/7sky PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7sky RCSB], [https://www.ebi.ac.uk/pdbsum/7sky PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7sky ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7skk|7skk]], [[7ski|7ski]]</div></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=7sky FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7sky OCA], [https://pdbe.org/7sky PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7sky RCSB], [https://www.ebi.ac.uk/pdbsum/7sky PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7sky ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/TOX1_BORPE TOX1_BORPE]] S1 is an NAD-dependent ADP-ribosyltransferase, which plays a crucial role in the pathogenesis of B.pertussis causing disruption of normal host cellular regulation. It catalyzes the ADP-ribosylation of a cysteine in the alpha subunit of host heterotrimeric G proteins. In the absence of G proteins it also catalyzes the cleavage of NAD(+) into ADP-ribose and nicotinamide. It irreversibly uncouples the G-alpha GTP-binding proteins from their membrane receptors. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Bordetella pertussis is the causative agent of whooping cough, a highly contagious respiratory disease. Pertussis toxin (PT), a major virulence factor secreted by B. pertussis, is an AB5-type protein complex topologically related to cholera toxin. The PT protein complex is internalized by host cells and follows a retrograde trafficking route to the endoplasmic reticulum (ER), where it subsequently dissociates. The released enzymatic S1 subunit is then translocated from the ER into the cytosol and subsequently ADP-ribosylates the inhibitory alpha-subunits (Galphai) of heterotrimeric G proteins, thus promoting dysregulation of G-protein coupled receptor (GPCR) signaling. However, the mechanistic details of the ADP-ribosylation activity of PT are not well understood. Here, we describe crystal structures of the S1 subunit in complex with nicotinamide adenine dinucleotide (NAD+), with NAD+ hydrolysis products ADP-ribose and nicotinamide, with NAD+ analog PJ34, and with a novel NAD+ analog formed upon S1 subunit crystallization with 3-amino benzamide (3AB) and NAD+, which we name benzamide amino adenine dinucleotide (BaAD). These crystal structures provide unprecedented insights into pre- and post-NAD+ hydrolysis steps of the ADP-ribosyltransferase activity of PT. We propose that these data may aid in rational drug design approaches and further development of PT-specific small molecule inhibitors. | |||
Crystal structures of pertussis toxin with NAD(+) and analogs provide structural insights into the mechanism of its cytosolic ADP-ribosylation activity.,Sakari M, Tran MT, Rossjohn J, Pulliainen AT, Beddoe T, Littler DR J Biol Chem. 2022 Apr 1:101892. doi: 10.1016/j.jbc.2022.101892. PMID:35378130<ref>PMID:35378130</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7sky" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Beddoe T]] | [[Category: Beddoe, T]] | ||
[[Category: Littler | [[Category: Littler, D R]] | ||
[[Category: Pulliainen A]] | [[Category: Pulliainen, A]] | ||
[[Category: Rossjohn J]] | [[Category: Rossjohn, J]] | ||
[[Category: Adp ribosyltransferase]] | |||
[[Category: Pertussis]] | |||
[[Category: Pertussis toxin]] | |||
[[Category: S1]] | |||
[[Category: Toxin]] | |||
[[Category: Transferase]] | |||
[[Category: Whooping cough]] | |||