ArticleBMC molecular and cell biology2021
Mechanism of hERG inhibition by gating-modifier toxin, APETx1, deduced by functional characterization.
Article in BMC molecular and cell biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 11 citations in OpenAlex.
- Ion Channel-Targeting Toxins: Structural Mechanisms of Activation, Inhibition, and Therapeutic Potential.Toxins · 2025Review
- Sea AnemoneMarine drugs · 2025Article
- Revealing the Diversity of Sequences, Structures, and Targets of Peptides from South China SeaMarine drugs · 2024Article
- Intranasal Administration of Bedaquiline-Loaded Fucosylated Liposomes Provides Anti-Tubercular Activity while Reducing the Potential for Systemic Side Effects.ACS infectious diseases · 2024Article
- Voltage-Gated KMarine drugs · 2024Review
- Diversity analysis of sea anemone peptide toxins in different tissues of Heteractis crispa based on transcriptomics.Scientific reports · 2024Article
- A Tale of Toxin Promiscuity: The Versatile Pharmacological Effects of Hcr 1b-2 Sea Anemone Peptide on Voltage-Gated Ion Channels.Marine drugs · 2022Article
- Function-Related Dynamics in Multi-Spanning Helical Membrane Proteins Revealed by Solution NMR.Membranes · 2021Review
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15 authors at 5 institutions in 1 country.
Funding
Abstract
backgroundHuman ether-à-go-go-related gene potassium channel 1 (hERG) is a voltage-gated potassium channel, the voltage-sensing domain (VSD) of which is targeted by a gating-modifier toxin, APETx1. APETx1 is a 42-residue peptide toxin of sea anemone Anthopleura elegantissima and inhibits hERG by stabilizing the resting state. A previous study that conducted cysteine-scanning analysis of hERG identified two residues in the S3-S4 region of the VSD that play important roles in hERG inhibition by APETx1. However, mutational analysis of APETx1 could not be conducted as only natural resources have been available until now. Therefore, it remains unclear where and how APETx1 interacts with the VSD in the resting state.
resultsWe established a method for preparing recombinant APETx1 and determined the NMR structure of the recombinant APETx1, which is structurally equivalent to the natural product. Electrophysiological analyses using wild type and mutants of APETx1 and hERG revealed that their hydrophobic residues, F15, Y32, F33, and L34, in APETx1, and F508 and I521 in hERG, in addition to a previously reported acidic hERG residue, E518, play key roles in the inhibition of hERG by APETx1. Our hypothetical docking models of the APETx1-VSD complex satisfied the results of mutational analysis.
conclusionsThe present study identified the key residues of APETx1 and hERG that are involved in hERG inhibition by APETx1. These results would help advance understanding of the inhibitory mechanism of APETx1, which could provide a structural basis for designing novel ligands targeting the VSDs of K
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