Biography & Net Worth: Find new potassium channels that selectively target pests

This image shows a small Drosophila melanogaster measuring 0.1 x 0.03 inches (2.5 x 0.8 mm). Image: Wikimedia Commons

Ion channels in the nervous system are one of the most important targets of insecticides. Understanding the structure of the channels is important for identifying new species-specific binding sites for insecticides. Researchers at the Maxplank Institute for Molecular Physiology in Dortmund, Germany, have worked with protein manufacturers Cube Biotech and Bayer CropScience to elucidate the structure and function of honeybee potassium ion channels. Their new insights reveal differences between human and insect channels, reveal how known compounds affect the channels, and suggest new target sites for drugs. This research could help pesticide manufacturers to design new drugs that are specifically suited to kill insects and parasites without affecting other animals, such as bees and mammals.

The sloping potassium channel is a large, complex protein located inside the common fruit fly cell membrane in Drosophila that selectively and rapidly transfers important potassium ions. They are found in all animals and are responsible for carrying out various functions. The most important are the brain and muscle cells. The critical role of potassium channels illustrates the importance of targeting the newly developed SLOPOK. Insecticides to help address the global problem of low efficiency due to increased pesticide resistance. However, there is always the risk of not aiming properly. “Ideally, insecticides are really insect-specific and we want to avoid drugs that are toxic and beneficial to humans, birds and other animals such as rodents. Insects are like bees,” said the Maxplank Institute for Molecular in Dortmund. Stephen Rounder, director of physiology and lead author of the study.

To design insect-specific drugs, scientists need a high-resolution structure of ion channels. Rauser et al. Cryo-electron microscopy (cryo-EM) is used to obtain open and closed protein structures and compare them with known human protein structures. “The difference between the human and insect channels is really small, but we have found a protein region that is unique to insects,” Raunser says.

Detailed map of potassium channels for drug discovery

One particular site of the channel, at the RCK2 pocket, is the amino acid it differs between Drosophila and humans. It’s in the gate ring at the bottom of the channel. The gating ring occurs inside the cell and when it is rich in calcium ions it picks up and initiates a cascade of rearrangements that open a central cavity for potassium ions to pass through. The RCK2 pocket changes shape as you switch between closed and open. Therefore, blocking channels in either state is a potentially perfect target for small molecules. Scientists have also identified other drug target sites that are not specific to insects. Among them, the S6 pocket appears closed and can be used to lock the channel. “We provide pharmaceutical scientists with a detailed map of potassium channels that can be used to create better, more selective insecticides,” concluded Raunser. Growth.

In addition, the researchers have used two known compounds, velcrogen and modepside, to solve the problem of channel cryo-EM structure. The fungal neurotoxin Velcrogen is a small molecule that fits snugly into the S6 pocket near the central cavity. Verruculogen narrows the channel and closes it. Another compound, modepside, a drug used against gastrointestinal worms in cats and dogs, binds near the S6 pocket. Nevertheless, it acts differently as an extra pass filter, making it difficult for potassium to pass through the channel in an optimal way. “These are how ligands you can manipulate the channel,” Raunser says.

Studies provide structural insight into how cholesterol regulates ion channels in the brain and alters their function.

for more information:
Tobias Raish et al, Small molecule regulation of Drosophila slow channels elucidated by cryo EM, nature communication (2021). DOI: 10.1038/s41467-021-27435-w

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Max Planck Society

Citation: Discovered a new potassium channel that selectively blocks insects obtained December 14, 2021 (2021) December 14, 2014 target)

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