MSGID: 1:317/3 6274a488   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    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   
      
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