Structure of central inflammation switch elucidated
Study by the University of Bonn could provide medicine with a powerful therapeutic tool

Date:
February 3, 2022
Source:
University of Bonn
Summary:
Researchers have elucidated the structure of a central cellular
inflammatory switch. Their work shows which site of the giant
protein called NLRP3 inhibitors can bind to. This opens the way
to develop new pharmaceuticals that could target inflammatory
diseases such as gout, type 2 diabetes or even Alzheimer's disease.



FULL STORY ========================================================================== Researchers at the Universities of Bonn and Regensburg have elucidated
the structure of a central cellular inflammatory switch. Their work
shows which site of the giant protein called NLRP3 inhibitors can bind
to. This opens the way to develop new pharmaceuticals that could target inflammatory diseases such as gout, type 2 diabetes or even Alzheimer's disease. The results are published in the journal Nature.


==========================================================================
In their study, the researchers investigated a protein molecule with
the cryptic abbreviation NLRP3. This is a kind of danger sensor in the
cell: It sounds the alarm when the cell is under stress, such as from
a bacterial infection or toxins.

NLRP3 then induces the formation of pores within the cellular membrane,
which ultimately results in the cell's death. Before that, however,
the sensor molecule stimulates the formation of inflammatory messenger substances that are released through the perforated membrane. These
so-called cytokines recruit more immune cells to the site and ensure
that cells in the surrounding area commit suicide -- thereby preventing
a bacterium or virus from further spreading.

"The result is a massive inflammatory response," explains study leader
Prof.

Dr. Matthias Geyer from the Institute of Structural Biology at the
University of Bonn. "This is certainly very useful for the defense against pathogens. But if this response is overdosed or triggered by even harmless cues, it can lead to chronic inflammatory diseases -- such as type II
diabetes, gout, Crohn's disease, or even dementias like Alzheimer's."
Targeted containment of inflammation Researchers around the globe are
therefore seeking for ways to target inflammatory processes without
disrupting the entire mechanism of the immune response. As early as 20
years ago, the US pharmaceutical company Pfizer published an interesting finding in this regard: Certain active substances prevent the release
of cytokines, the most important inflammatory messengers.

How these CRIDs (Cytokine Release Inhibitory Drugs) do this, however,
was unknown until now.



==========================================================================
It has been known for several years that CRIDs somehow prevent cellular
danger sensors from sounding the alarm. "We have now discovered the
way in which they exert this effect," explains Geyer's colleague Inga Hochheiser. This involved isolating large amounts of NLRP3 from cells, purifying it, and adding the inhibitor CRID3. Hochheiser dropped minute portions of this mixture onto a carrier and then froze them rapidly.

This method creates a thin film of ice containing millions of NLRP3
molecules to which CRID3 is bound. These can be observed with an electron microscope.

Since the molecules fall differently as they drop, different sides of
them can be seen under the microscope. "These views can be combined to
create a three- dimensional image," Hochheiser explains.

The cryo-EM images allow a detailed insight into the structure of the
hazard sensor inactivated by CRID3. They reveal that NLRP3 in its inactive
form assembles into a mega-molecule. It consists of ten NLRP3 units that together form a kind of cage. "The most exciting result of our work,
however, is that we were able to identify the CRID3 molecule docked into
its binding site," Geyer is pleased to report. "That was a tough nut that
many groups worldwide have been trying to crack." Inhibitor prevents
the activation of the giant molecule The binding sites (structural
biologists also speak of "pockets") are located inside the cage. Each of
the ten NLRP3 units has one of these pockets. When occupied by CRID3, the inhibitor blocks a flap mechanism required for NLRP3 activation. Similar
to a blooming rose, which can only be visited by a bee in this state,
certain parts of the NLRP3 protein reach the surface of the cage when
the flap is turned over and thus become accessible.

NLRP3 is a representative of an entire family of similar proteins. Each of
them presumably performs its very specific task in different inflammatory processes.

"Based on our research, we believe that the pockets of all these NLRPs
are different," Geyer says. "A specific inhibitor can therefore probably
be found for each of them." This gives researchers a whole arsenal of
potential new weapons against diverse, inflammatory diseases.

For example, the current work allows a targeted search for more effective alternatives to CRID3 that also have fewer side effects. But that is just
the beginning, says Geyer, who is also a member of the ImmunoSensation2
Cluster of Excellence at the University of Bonn. "I am convinced that our
study opens up a fruitful new field of research that will keep researchers
busy for decades to come." Participating institutions and funding: The
study was funded by the German Research Foundation (DFG) and by EU funds
under the iNEXT-Discovery and Instruct-ERIC initiatives. The cryo-EM
images for structure elucidation were recorded at EMBL in Heidelberg.

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


========================================================================== Journal Reference:
1. Inga V. Hochheiser, Michael Pilsl, Gregor Hagelueken, Jonas
Moecking,
Michael Marleaux, Rebecca Brinkschulte, Eicke Latz, Christoph
Engel, Matthias Geyer. Structure of the NLRP3 decamer bound
to the cytokine release inhibitor CRID3. Nature, 2022; DOI:
10.1038/s41586-022-04467-w ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220203122903.htm

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