Finding new channels to selectively target insect pests – sciencedaily

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The ion channels of the nervous system are among the most important targets of insecticides. Understanding the structure of channels is essential for the identification of novel species-specific binding sites of agrochemicals. Researchers have revealed the structure and function of a potassium ion channel in fruit flies. Their newly obtained knowledge reveals the differences between human and insect channels, explains how known compounds affect the channel, and suggests new target sites for drugs. The research could help pesticide makers design new drugs that can specifically kill pests and parasites without affecting other animals like bees and mammals.

Slowpoke potassium channels in drosophila, the common fruit fly, are huge and complex proteins that are found inside the cell membrane and selectively and rapidly transport vital potassium ions through it. They are found in all animals and are responsible for performing various tasks, primarily in the brain and muscle cells. The essential roles of potassium channels mean the importance of targeting Slowpoke with newly developed insecticides to help overcome the global problem of declining efficacy due to increasing resistance to pesticides. Yet there is always the risk of not aiming correctly: “Ideally, you want the insecticides to be really specific to the insect pest, avoiding drugs toxic to humans, or other animals, such as birds.” , rodents and beneficial insects like bees, “says Stefan Raunser, director of the Max Planck Institute for Molecular Physiology in Dortmund and lead author of the study.

In order to design drugs specific to insect pests, scientists need high-resolution structures of ion channels. Raunser and his colleagues used electronic cryomicroscopy (cryo-EM) to obtain the structures of the protein in the open and closed state and compared them to the structures of human proteins already known. “The difference between human and insect channels is really minimal, but we have found protein regions specific to insects,” says Raunser.

Detailed map of the potassium channel for drug discovery

A specific site of the channel, called the RCK2 pocket, has amino acids that differ between drosophila and humans. It is located at the locking ring at the bottom of the channel. The trigger ring is inside the cell, picks up calcium ions when they are abundant, and triggers a cascade of rearrangements that open up the central cavity for the passage of potassium ions. The RCK2 pocket changes shape when it goes from the closed state to the open state. Therefore, it is a potentially perfect target for small molecules to block the channel in either state. Scientists have also identified other drug target sites that are less specific to insects. Among them, the S6 pocket appears in the closed state and could be used to lock the channel. “We are providing pharmaceutical scientists with a detailed map of the potassium channel, which they can use to make better, highly selective insecticides,” concludes Raunser.

In addition, the researchers also solved the cryo-EM structures of the channel with two known compounds, verruculogen and emodepside. The verruculogenic fungal neurotoxin is a small molecule which fits perfectly into the S6 pocket, near the central cavity. Verruculogen keeps the canal narrow, locking it in the closed state. Another compound, emodepside, a drug used against gastrointestinal worms in cats and dogs, also binds near the S6 pocket. Yet, it acts differently, as an additional pass filter, making it difficult for the optimal passage of potassium through the canal. “It’s important to understand how these ligands can manipulate the channel,” says Raunser.

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Materials provided by Max Planck Institute for Molecular Physiology. Note: Content can be changed for style and length.

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