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==A lid blocking mechanism of a cone snail toxin revealed at the atomic level== | ==A lid blocking mechanism of a cone snail toxin revealed at the atomic level== | ||
<StructureSection load='6yht' size='340' side='right'caption='[[6yht]]' scene=''> | <StructureSection load='6yht' size='340' side='right'caption='[[6yht]], [[Resolution|resolution]] 2.15Å' 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=6YHT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YHT FirstGlance]. <br> | <table><tr><td colspan='2'>[[6yht]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Conus_cocceus Conus cocceus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YHT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YHT 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=6yht FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yht OCA], [https://pdbe.org/6yht PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yht RCSB], [https://www.ebi.ac.uk/pdbsum/6yht PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yht 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=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6yht FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yht OCA], [https://pdbe.org/6yht PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yht RCSB], [https://www.ebi.ac.uk/pdbsum/6yht PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yht ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Many venomous organisms carry in their arsenal short polypeptides that block K(+) channels in a highly selective manner. These toxins may compete with the permeating ions directly via a "plug" mechanism or indirectly via a "pore-collapse" mechanism. An alternative "lid" mechanism was proposed but remained poorly defined. Here we study the Drosophila Shaker channel block by Conkunitzin-S1 and Conkunitzin-C3, two highly similar toxins derived from cone venom. Despite their similarity, the two peptides exhibited differences in their binding poses and biophysical assays, implying discrete action modes. We show that while Conkunitzin-S1 binds tightly to the channel turret and acts via a "pore-collapse" mechanism, Conkunitzin-C3 does not contact this region. Instead, Conk-C3 uses a non-conserved Arg to divert the permeant ions and trap them in off-axis cryptic sites above the SF, a mechanism we term a "molecular-lid". Our study provides an atomic description of the "lid" K(+) blocking mode and offers valuable insights for the design of therapeutics based on venom peptides. | |||
A Molecular Lid Mechanism of K(+) Channel Blocker Action Revealed by a Cone Peptide.,Saikia C, Dym O, Altman-Gueta H, Gordon D, Reuveny E, Karbat I J Mol Biol. 2021 Aug 20;433(17):166957. doi: 10.1016/j.jmb.2021.166957. Epub 2021, Mar 24. PMID:33771569<ref>PMID:33771569</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6yht" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Conus cocceus]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Altman-Gueta H]] | [[Category: Altman-Gueta, H]] | ||
[[Category: Dym O]] | [[Category: Dym, O]] | ||
[[Category: Frolow F]] | [[Category: Frolow, F]] | ||
[[Category: Gordon D]] | [[Category: Gordon, D]] | ||
[[Category: Gurevitz M]] | [[Category: Gurevitz, M]] | ||
[[Category: Karbat I]] | [[Category: Karbat, I]] | ||
[[Category: Reuveny E]] | [[Category: Reuveny, E]] | ||
[[Category: Saikia C]] | [[Category: Saikia, C]] | ||
[[Category: Conkunitzin-3]] | |||
[[Category: Toxin]] | |||
Revision as of 18:48, 27 October 2021
A lid blocking mechanism of a cone snail toxin revealed at the atomic levelA lid blocking mechanism of a cone snail toxin revealed at the atomic level
Structural highlights
Publication Abstract from PubMedMany venomous organisms carry in their arsenal short polypeptides that block K(+) channels in a highly selective manner. These toxins may compete with the permeating ions directly via a "plug" mechanism or indirectly via a "pore-collapse" mechanism. An alternative "lid" mechanism was proposed but remained poorly defined. Here we study the Drosophila Shaker channel block by Conkunitzin-S1 and Conkunitzin-C3, two highly similar toxins derived from cone venom. Despite their similarity, the two peptides exhibited differences in their binding poses and biophysical assays, implying discrete action modes. We show that while Conkunitzin-S1 binds tightly to the channel turret and acts via a "pore-collapse" mechanism, Conkunitzin-C3 does not contact this region. Instead, Conk-C3 uses a non-conserved Arg to divert the permeant ions and trap them in off-axis cryptic sites above the SF, a mechanism we term a "molecular-lid". Our study provides an atomic description of the "lid" K(+) blocking mode and offers valuable insights for the design of therapeutics based on venom peptides. A Molecular Lid Mechanism of K(+) Channel Blocker Action Revealed by a Cone Peptide.,Saikia C, Dym O, Altman-Gueta H, Gordon D, Reuveny E, Karbat I J Mol Biol. 2021 Aug 20;433(17):166957. doi: 10.1016/j.jmb.2021.166957. Epub 2021, Mar 24. PMID:33771569[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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