Structure–function relationships in ShKT domain peptides: ShKT‐Ts1 from the sea anemone Telmatactis stephensoni

Author:

Sanches Karoline12,Ashwood Lauren M.3,Olushola‐Siedoks Abisola Ave‐Maria1,Wai Dorothy C. C.1,Rahman Arfatur1,Shakeel Kashmala4,Naseem Muhammad Umair4,Panyi Gyorgy4,Prentis Peter J.35,Norton Raymond S.12ORCID

Affiliation:

1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences Monash University Parkville Victoria Australia

2. ARC Centre for Fragment‐Based Design Monash University Parkville Victoria Australia

3. School of Biology and Environmental Science, Faculty of Science Queensland University of Technology Brisbane Queensland Australia

4. Department of Biophysics and Cell Biology, Faculty of Medicine University of Debrecen Debrecen Hungary

5. Centre for Agriculture and the Bioeconomy Queensland University of Technology Brisbane Queensland Australia

Abstract

AbstractDiverse 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 (KV1.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 KV1.x, while others do not. Mutagenesis studies have shown that a Lys–Tyr (KY) dyad plays a key role in KV1.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 KV1.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 KV1.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 KV1.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.

Funder

Australian Research Council

Publisher

Wiley

Subject

Molecular Biology,Biochemistry,Structural Biology

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