8sed
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8sed]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Telmatactis_stephensoni Telmatactis stephensoni]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8SED OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8SED FirstGlance]. <br> | <table><tr><td colspan='2'>[[8sed]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Telmatactis_stephensoni Telmatactis stephensoni]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8SED OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8SED FirstGlance]. <br> | ||
| - | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</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=8sed FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8sed OCA], [https://pdbe.org/8sed PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8sed RCSB], [https://www.ebi.ac.uk/pdbsum/8sed PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8sed ProSAT]</span></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=8sed FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8sed OCA], [https://pdbe.org/8sed PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8sed RCSB], [https://www.ebi.ac.uk/pdbsum/8sed PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8sed ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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Diverse structural scaffolds have been described in peptides from sea anemones, with the ShKT domain being a common scaffold first identified in ShK toxin from Stichodactyla helianthus. ShK is a potent blocker of voltage-gated potassium channels (K(V) 1.x), and an analog, ShK-186 (dalazatide), has completed Phase 1 clinical trials in plaque psoriasis. The ShKT domain has been found in numerous other species, but only a tiny fraction of ShKT domains has been characterized functionally. Despite adopting the canonical ShK fold, some ShKT peptides from sea anemones inhibit K(V) 1.x, while others do not. Mutagenesis studies have shown that a Lys-Tyr (KY) dyad plays a key role in K(V) 1.x blockade, although a cationic residue followed by a hydrophobic residue may also suffice. Nevertheless, ShKT peptides displaying an ShK-like fold and containing a KY dyad do not necessarily block potassium channels, so additional criteria are needed to determine whether new ShKT peptides might show activity against potassium channels. In this study, we used a combination of NMR and molecular dynamics (MD) simulations to assess the potential activity of a new ShKT peptide. We determined the structure of ShKT-Ts1, from the sea anemone Telmatactis stephensoni, examined its tissue localization, and investigated its activity against a range of ion channels. As ShKT-Ts1 showed no activity against K(V) 1.x channels, we used MD simulations to investigate whether solvent exposure of the dyad residues may be informative in rationalizing and potentially predicting the ability of ShKT peptides to block K(V) 1.x channels. We show that either a buried dyad that does not become exposed during MD simulations, or a partially exposed dyad that becomes buried during MD simulations, correlates with weak or absent activity against K(V) 1.x channels. Therefore, structure determination coupled with MD simulations, may be used to predict whether new sequences belonging to the ShKT family may act as potassium channel blockers. | Diverse structural scaffolds have been described in peptides from sea anemones, with the ShKT domain being a common scaffold first identified in ShK toxin from Stichodactyla helianthus. ShK is a potent blocker of voltage-gated potassium channels (K(V) 1.x), and an analog, ShK-186 (dalazatide), has completed Phase 1 clinical trials in plaque psoriasis. The ShKT domain has been found in numerous other species, but only a tiny fraction of ShKT domains has been characterized functionally. Despite adopting the canonical ShK fold, some ShKT peptides from sea anemones inhibit K(V) 1.x, while others do not. Mutagenesis studies have shown that a Lys-Tyr (KY) dyad plays a key role in K(V) 1.x blockade, although a cationic residue followed by a hydrophobic residue may also suffice. Nevertheless, ShKT peptides displaying an ShK-like fold and containing a KY dyad do not necessarily block potassium channels, so additional criteria are needed to determine whether new ShKT peptides might show activity against potassium channels. In this study, we used a combination of NMR and molecular dynamics (MD) simulations to assess the potential activity of a new ShKT peptide. We determined the structure of ShKT-Ts1, from the sea anemone Telmatactis stephensoni, examined its tissue localization, and investigated its activity against a range of ion channels. As ShKT-Ts1 showed no activity against K(V) 1.x channels, we used MD simulations to investigate whether solvent exposure of the dyad residues may be informative in rationalizing and potentially predicting the ability of ShKT peptides to block K(V) 1.x channels. We show that either a buried dyad that does not become exposed during MD simulations, or a partially exposed dyad that becomes buried during MD simulations, correlates with weak or absent activity against K(V) 1.x channels. Therefore, structure determination coupled with MD simulations, may be used to predict whether new sequences belonging to the ShKT family may act as potassium channel blockers. | ||
| - | Structure-function relationships in ShKT domain peptides: ShKT-Ts1 from the sea anemone Telmatactis stephensoni.,Sanches K, Ashwood LM, Olushola-Siedoks AA, Wai DCC, Rahman A, Shakeel K, Naseem MU, Panyi G, Prentis PJ, Norton RS Proteins. | + | Structure-function relationships in ShKT domain peptides: ShKT-Ts1 from the sea anemone Telmatactis stephensoni.,Sanches K, Ashwood LM, Olushola-Siedoks AA, Wai DCC, Rahman A, Shakeel K, Naseem MU, Panyi G, Prentis PJ, Norton RS Proteins. 2024 Feb;92(2):192-205. doi: 10.1002/prot.26594. Epub 2023 Oct 4. PMID:37794633<ref>PMID:37794633</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Current revision
Structure of a new ShKT peptide from the sea anemone Telmatactis stephensoni: ShKT-Ts1
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