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Small but essential – recognition of peptides in receptor families

Researchers discover molecular mechanisms of signal recognition in the neuropeptide system

The human body is made up of trillions of cells that are constantly communicating with each other. Recipient proteins on the cell surface, so-called receptors, play a central role in this communication process. They are used particularly frequently as target structures for drugs and are therefore intensively researched. There are often entire families of receptors. Both the signal messengers and the receptors are very similar to one another, so it is not clear how the signals are differentiated from one another at the molecular level. In a joint research project, scientists from the Collaborative Research Center 1423 at the University of Leipzig, the Hangzhou Institute for Advanced Study and the Chinese Academy of Sciences in Shanghai have now succeeded in finding high-resolution structures for the neuropeptide Y (NPY) receptor family for three related im to obtain signal complexes that occur naturally in the body and thus to shed light on the small but essential differences. The researchers have now published their new findings in the renowned journal Science Advances.

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 messenger substances both locally in the tissue, 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 appearing in different situations: while NPY associated with Y1R in the brain signals hunger, PP bound to Y4R mediates a strong satiety signal. NPY receptors are also of interest for modern cancer therapies. A high number of Y1Rs is characteristic of breast cancer cells, which means that NPY variants that only bind to this receptor could be used selectively to transport active substances into these cells in a targeted manner. In healthy breast tissue, on the other hand, the Y2R receptor is the most common. This should be "bypassed" in order to protect the healthy tissue.

For the development of targeted active ingredients, it is therefore of great importance to know the molecular blueprint of these complexes and the underlying regulatory mechanisms. In addition to the molecular structures made visible by cryo-electron microscopy by Prof. Qiang Zhao from the Hangzhou Institute for Advanced Study and Prof. Beili Wu from the Chinese Academy of Sciences, Prof. Dr. Annette Beck-Sickinger and Dr. Anette Kaiser from the University of Leipzig carried out biochemical studies that better shed light on the complex binding mechanisms of the peptides to their receptors and underpin the results of the structural investigations. The relevant areas of peptide and receptor could be found in the complex.

The working groups have been conducting joint research in this research field for more than ten years, and the results build on extensive preliminary work. This makes this third joint publication by the working groups all the more valuable. With the help of a novel test system, it was shown that the peptides use different "docking pathways" and that this can lead to different signals in the cell. The flexibility, the mobility of the complexes in certain areas play an important role. Prof. Annette Beck-Sickinger says: “So part of the flexibility of the peptide and receptor is also retained in the bound state. The causes and consequences of this are now being further researched in further studies in the SFB 1423, as well as the question of which other factors have an influence on the recognition between peptides and receptors.”

The study of the NPY receptor family with its endogenous ligands and other clinically relevant compounds is a focus of the Collaborative Research Center 1423 coordinated at the University of Leipzig. It is a four-year research facility funded by the German Research Foundation (DFG) in which four funding institutions are involved: University of Leipzig , the Martin Luther University Halle-Wittenberg, the Charité – Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine in Berlin.
Researchers from biochemical, biomedical and computational contexts are collaborating across the boundaries of their respective institutions and disciplines to gain a comprehensive understanding of the impact of structural dynamics on GPCR function. The latest findings and approaches in GPCR research will also be presented at the international conference 4GPCRnet '22, co-organized by the SFB1423. This high-level meeting will take place from 26 to 29 September 2022 on the Leipzig University campus at Augustusplatz.

Original title of publication in “Science Advances”:

"Receptor-specific recognition of NPY peptides revealed by structures of NPY receptors", DOI: 10.1126/sciadv.abm1232

Further information
Prof. Dr. Annette Beck-Sickinger - Spokesperson of the SFB1423 & project manager B01, A04, Z03
Institute for Biochemistry at the University of Leipzig
Phone: +49 341 97-36901

Source: Press release University of Leipzig from April 05.05.2022th, XNUMX

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