8SED
Structure of a new ShKT peptide from the sea anemone Telmatactis stephensoni: ShKT-Ts1
Summary for 8SED
| Entry DOI | 10.2210/pdb8sed/pdb |
| NMR Information | BMRB: 51896 |
| Descriptor | ShKT peptide ShKT-Ts1 (1 entity in total) |
| Functional Keywords | toxin |
| Biological source | Telmatactis stephensoni (sea anemone) |
| Total number of polymer chains | 1 |
| Total formula weight | 4243.81 |
| Authors | Sanches, K.,Siedoks, A.A.,Wai, D.C.C.,Norton, R.S. (deposition date: 2023-04-09, release date: 2023-10-18, Last modification date: 2024-10-30) |
| Primary citation | Sanches, K.,Ashwood, L.M.,Olushola-Siedoks, A.A.,Wai, D.C.C.,Rahman, A.,Shakeel, K.,Naseem, M.U.,Panyi, G.,Prentis, P.J.,Norton, R.S. Structure-function relationships in ShKT domain peptides: ShKT-Ts1 from the sea anemone Telmatactis stephensoni. Proteins, 92:192-205, 2024 Cited by PubMed Abstract: 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 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 1.x, while others do not. Mutagenesis studies have shown that a Lys-Tyr (KY) dyad plays a key role in K 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 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 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 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. PubMed: 37794633DOI: 10.1002/prot.26594 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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