Study shows how bioactive substance inhibits important receptor
Results raise hope for new drugs against cancer and brain diseases
Date:
March 25, 2022
Source:
University of Bonn
Summary:
The A2A receptor regulates how vigorously the innate immune system
attacks diseased cells. Researchers have now been able to show for
the first time how an important inhibitor binds to the receptor. In
the future, the results will facilitate the targeted search for
molecules that give the innate immune system more punch. These
could for instance be used in the fight against cancer, but also
against brain diseases such as Alzheimer's or Parkinson's disease.
FULL STORY ==========================================================================
The A2A receptor regulates how vigorously the innate immune system
attacks diseased cells. Researchers at the University of Bonn have now
been able to show for the first time how an important inhibitor binds
to the receptor. In the future, the results will facilitate the targeted
search for molecules that give the innate immune system more punch. These
could for instance be used in the fight against cancer, but also against
brain diseases such as Alzheimer's or Parkinson's disease. The final
version of the study has been published in the journal Angewandte Chemie International Edition.
========================================================================== Anyone who enjoys reading thrillers knows: Before thieves break into a
mansion, they like to toss a juicy chop over the fence, in which they have hidden a few sleeping pills. When the watchdogs get down to their second dinner, they succumb to deep slumber shortly thereafter. The jewels of
the lady of the house change hands much more unperturbed after that.
Tumor cells often proceed in a very similar way: They cast out
sleeping pills that paralyze the immune system. More specifically, they surround themselves with a cloud of adenosine, an important endogenous messenger. In this way, they disable the body's own "killer cells,"
which would otherwise cause the cancer cells to die.
This is because the adenosine molecules bind to tiny antennae on the
surface of the immune cells, the A2A receptors (the abbreviation stands
for "type 2A adenosine receptors"). This knocks out the defensive troops,
so to speak.
Researchers around the globe are therefore looking for molecules that
can block the A2A receptor and prevent the paralyzing effect of adenosine.
Bombardment with X-rays "Our study should make this search a lot easier," explains Prof. Dr. Christa Mu"ller of the Pharmaceutical Institute of the University of Bonn. "We have added novel variants of a known inhibitor,
a substance called preladenant, to the A2A receptor. Then we created
crystals from the receptor-inhibitor complexes -- it's the first time in
the world that this has been achieved with preladenant-like substances." Crystallization made it possible to elucidate the structure of the
complex. "To do this, we bombard the compound with X-rays," explains
Tobias Claff, who performed the main part of the experiments. "The
crystal diffracts the rays.
The way it does this then allows us to deduce the spatial structure of
the complex -- right down to the arrangement of individual atoms and
their interactions."
==========================================================================
In this way, the researchers were able to show to which points of the
A2A receptor preladenant binds. With this knowledge, it is now possible
to specifically modify the inhibitor to give it better properties. In
addition to having the strongest possible effect, drugs should for example
not be broken down too quickly. They also need to be able to reach the
place where they are supposed to do their work -- in this case, the
brain. "Our study will make it much easier to optimize the substance,"
Claff says with optimism.
A2A belongs to a group of receptors that regulate key functions in
the body.
They span the membrane of cells. The part of them that sits on the
outside of the membrane serves as a sensor, receiving molecular signals
like an antenna.
When it does, it triggers specific reactions with its part that protrudes
into the cell. This then activates certain genes, for example.
Dye bound to the inhibitory molecule "These receptors are immensely
important because of their central position," says Christa Mu"ller,
who is also a member of the Transdisciplinary Research Areas (TRA)
"Building Blocks of Matter" and "Life and Health." "Many of them,
however, are unfortunately relatively unstable. This is unfavorable for
X-ray structural analyses -- crystallization takes days, sometimes even
weeks." The researchers therefore specifically modified the A2A receptor
at a single point, making it considerably more stable.
Additionally, they succeeded in attaching a dye to the preladenant with a
kind of molecular string. "This allows us to control where in the tissue preladenant attaches to the A2A receptor," Mu"ller says. At the same time,
the length and flexibility of the nanostring ensures that the inhibitor
is not obstructed from binding to the receptor.
Both advances could also serve as models for work with other receptors
that belong to the same group. "The methods we have developed in Bonn in
recent years will allow us to elucidate the structure of such and other
cell membrane proteins in the future," the pharmacist is convinced. "There aren't many research facilities that can do this kind of structural
analysis of extremely complex molecules." Participating institutions
and funding: In addition to the University of Bonn, the Centre for
Structural Systems Biology (CSSB) and Forschungszentrum Ju"lich were
involved. The study was funded by the German Research Foundation and
the Federal Ministry of Education and Research.
========================================================================== Story Source: Materials provided by University_of_Bonn. Note: Content
may be edited for style and length.
========================================================================== Journal Reference:
1. Tobias Claff, Tim A. Klapschinski, Udaya K. Tiruttani Subhramanyam,
Victoria J. Vaassen, Jonathan G. Schlegel, Christin Vielmuth, Jan H.
Voss, Jo"rg Labahn, Christa E. Mu"ller. Single Stabilizing
Point Mutation Enables High‐Resolution Co‐Crystal
Structures of the Adenosine A 2A Receptor with Preladenant
Conjugates. Angewandte Chemie International Edition, 2022; DOI:
10.1002/anie.202115545 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/03/220325122713.htm
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