Finding new channels to selectively target pest insects

Date:
December 14, 2021
Source:
Max Planck Institute of Molecular Physiology
Summary:
Ion channels in the nervous system are among the most important
targets for insecticides. Understanding the structure of the
channels is key 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 insights reveal the differences between
human and insect channels, explain how known compounds affect the
channel and propose new target sites for drugs. The research could
help pesticide manufacturers design new drugs apt to specifically
kill pest insects and parasites without affecting other animals
like bees and mammals.



FULL STORY ==========================================================================
Ion channels in the nervous system are among the most important targets
for insecticides. Understanding the structure of the channels is key
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 insights reveal the differences between human and insect channels, explain how known compounds affect the channel and propose new target sites for drugs. The research
could help pesticide manufacturers design new drugs apt to specifically
kill pest insects and parasites without affecting other animals like
bees and mammals.


==========================================================================
The Slowpoke potassium channels in Drosophila, the common fruit fly,
are huge and complex proteins that sit inside the cellular membrane
and selectively and rapidly transport vital potassium ions through
it. They are found in all animals and are responsible for completing
various tasks, most importantly in the brain and in muscle cells. The
essential roles of the potassium channels signify the importance of
targeting Slowpoke with newly developed insecticides in order to help
overcome the global problem concerning the decrease in efficiency due to
the growing pesticide resistance. Yet, there is always the risk of not
aiming properly: "Ideally, you want insecticides to be really specific
to the pest insect, avoiding drugs that are toxic for humans, or other
animals, such as birds, rodents and beneficial insects like bees,"
says Stefan Raunser, Director at the Max Planck Institute of Molecular Physiology in Dortmund, and lead author of the study.

In order to design drugs that are specific for pest insects, scientists
need high-resolution structures of the ion channels. Raunser and
colleagues used cryo-electron microscopy (cryo-EM) to obtain the
structures of the protein in the open and in the closed states and
compared them with structures of the human proteins that are already
known. "The difference between human and insect channels are really tiny,
but we found protein regions that are specific to insects," says Raunser.

Detailed map of the potassium channel for drug discovery One specific site
of the channel, named RCK2 pocket, has amino acids that differ between Drosophila and humans. It is located at the gating ring at the bottom of
the channel. The gating ring sits inside the cell, picks up calcium ions
when abundant and kicks off a cascade of rearrangements that open up the central cavity for potassium ions to pass through. The RCK2 pocket changes
its shape as it shifts between closed and open states. Therefore, it is
a potentially perfect target for small molecules to block the channel
in either state. Scientists pinpointed also other less insect-specific
drug target sites.

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.

Additionally, the researchers also solved the cryo-EM structures of the
channel with two known compounds, verruculogen and emodepside. The fungal neurotoxin verruculogen is a small molecule that fits perfectly in the
S6 pocket, close to the central cavity. Verruculogen keeps the channel
narrow, locking it in the closed state. Another compound, emodepside,
a drug used against gastrointestinal worms in cats and dogs, also binds
close to the S6 pocket.

Yet, it acts differently, as an additional passing filter, making it
difficult for potassium to go through the channel in an optimal way. "It's important to understand how these ligands can manipulate the channel,"
says Raunser.

========================================================================== Story Source: Materials provided by Max_Planck_Institute_of_Molecular_Physiology. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Tobias Raisch, Andreas Brockmann, Ulrich Ebbinghaus-Kintscher, Jo"rg
Freigang, Oliver Gutbrod, Jan Kubicek, Barbara Maertens,
Oliver Hofnagel, Stefan Raunser. Small molecule modulation of the
Drosophila Slo channel elucidated by cryo-EM. Nature Communications,
2021; 12 (1) DOI: 10.1038/ s41467-021-27435-w ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211214152144.htm

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