Small changes -- but essential! How peptides are recognized in receptors
Researchers discover molecular mechanisms of signal recognition of the neuropeptide system

Date:
May 5, 2022
Source:
Universita"t Leipzig
Summary:
The human body consists of trillions of cells that constantly
communicate with each other. A central role in this communication
process is played by receptor proteins on the cell surface. Since
they often serve as drug targets, they have been the subject of
intensive research. Often there are whole families of receptors. The
signal messengers as well as the receptors are very similar to
each other, so it is not clear how the signals are distinguished
from each other at the molecular level. Now, scientists have
succeeded in determining high-resolution structures for three
related signalling complexes that occur naturally in the body for
the neuropeptide Y (NPY) receptor family, thus shedding light on
the 'small but essential differences'.



FULL STORY ==========================================================================
The human body consists of trillions of cells that constantly communicate
with each other. A central role in this communication process is played
by receptor proteins on the cell surface. Since they often serve as drug targets, they have been the subject of intensive research. Often there
are whole families of receptors. The signal messengers as well as the
receptors are very similar to each other, so it is not clear how the
signals are distinguished from each other at the molecular level. Now,
in a joint research project, scientists from Collaborative Research Centre
1423 at Leipzig University, the Hangzhou Institute for Advanced Study and
the Chinese Academy of Sciences in Shanghai have succeeded in determining high-resolution structures for three related signalling complexes that
occur naturally in the body for the neuropeptide Y (NPY) receptor family,
thus shedding light on the "small but essential differences."

==========================================================================
The NPY family consists of a total of three related peptide ligands:
NPY, PP and PYY, which have different functions in the body. These act
as messengers both locally in the tissues, especially in the brain,
and via the bloodstream.

They bind to four different receptors (Y1R, Y2R, Y4R and Y5R), with
different combinations of peptide ligand and receptor occurring in
different situations: while NPY in conjunction with Y1R signals hunger in
the brain, PP bound to Y4R conveys a strong satiety signal. NPY receptors
are also of interest for modern cancer therapies. A high number of Y1R
is characteristic for breast cancer cells, which is why NPY variants
that selectively bind only to this receptor could be used to deliver
drugs specifically to these cells. Healthy breast tissue, on the other
hand, contains mainly the receptor Y2R. It would make sense to 'bypass'
this in order to spare the healthy tissue.

To be able to develop targeted active substances, it is therefore highly important to know the molecular blueprint of these complexes and the
underlying regulatory mechanisms. In addition to the molecular structures visualised by Professor Qiang Zhao from the Hangzhou Institute for
Advanced Study and Professor Beili Wu of the Chinese Academy of Sciences
using cryogenic electron microscopy, Professor Annette Beck-Sickinger
and Dr Anette Kaiser of Leipzig University conducted biochemical studies
that shed more light on the complex mechanisms that bind the peptides to
their receptors and supported the results of the structural studies. It
was possible to find the relevant regions in the peptides and receptors
in the complex.

The working groups have been conducting joint research in this field for
over ten years, and these new results build on extensive preliminary
work. This makes this joint publication -- the third by the working
groups -- all the more valuable. This is because a novel test system
showed that the peptides use different 'docking pathways' and that this
can lead to different signals in the cell. The flexibility and mobility
of the complexes in certain areas plays an important role. Professor
Annette Beck-Sickinger explains: "Some of the flexibility of the
peptide and receptor is thus retained even in the bound state. The
causes and consequences of this are now being further investigated
in ongoing studies in CRC 1423, as is the question of what other
factors influence the recognition between peptides and receptors."
The investigation of this NPY receptor family with its endogenous
ligands as well as other clinically relevant compounds is one focus
of Collaborative Research Centre 1423. It is a research project being
funded for four years by the German Research Foundation (DFG), in which
four institutions are involved: Leipzig University, the Martin Luther University Halle-Wittenberg, Charite' - - Universita"tsmedizin Berlin and
the Max Delbru"ck Center for Molecular Medicine in Berlin. Researchers
from these institutions with backgrounds in biochemistry, biomedicine and computational science are collaborating on an interdisciplinary basis to
gain a comprehensive understanding of the effects of structural dynamics
on the GPCR function. The latest findings and approaches in GPCR research
will also be presented at 4GPCRnet '22, an international conference co-organised by CRC 1423. This high-level meeting will take place on the Leipzig University company at Augustusplatz from 26 to 29 September 2022.


========================================================================== Story Source: Materials provided by Universita"t_Leipzig. Original
written by Susann Huster.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Tingting Tang, Qiuxiang Tan, Shuo Han, Anne Diemar, Kristin Lo"bner,
Hongyu Wang, Corinna Schu"ss, Victoria Behr, Karin Mo"rl, Mu
Wang, Xiaojing Chu, Cuiying Yi, Max Keller, Jacob Kofoed, Steffen
Reedtz-Runge, Anette Kaiser, Annette G. Beck-Sickinger, Qiang Zhao,
Beili Wu. Receptor- specific recognition of NPY peptides revealed
by structures of NPY receptors. Science Advances, 2022; 8 (18)
DOI: 10.1126/sciadv.abm1232 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/05/220505114705.htm

--- up 9 weeks, 3 days, 10 hours, 50 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)