MSGID: 1:317/3 6413ece7   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Protein engineers navigate toward more targeted therapeutics    
    New research on protein receptors could lead to breakthroughs in   
   improving drug delivery.    
      
     Date:   
         March 16, 2023   
     Source:   
         University of Minnesota   
     Summary:   
         Researchers uncovered the role of the third intracellular loop in   
         the G protein-coupled receptors' signaling mechanism, which could   
         lead to a more targeted approach to drug discovery and a paradigm   
         shift for new therapeutics.   
      
      
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   FULL STORY   
   ==========================================================================   
   More than a third of FDA-approved drugs work by targeting a G   
   protein-coupled receptor, or GPCR. The human body has more than 800   
   types of GPCRs that provide cells with information about the external   
   environment to calibrate responses.   
      
   Drugs that either block or activate GPCRs are used to treat a wide range   
   of diseases including hypertension, pain and inflammation. Most drugs   
   bind to the outside of the receptor, but this can result in adverse side   
   effects since receptors often resemble one another.   
      
      
   ==========================================================================   
   In a new study published in Nature, Sivaraj Sivaramakrishnan, a professor   
   in the College of Biological Sciences, along with graduate student Fred   
   Sadler and co-authors Michael Ritt and Yatharth Sharma, uncovered the   
   role of the third intracellular loop in the GPCR's signaling mechanism,   
   suggesting the possibility of a more targeted approach to drug discovery   
   and a paradigm shift for new therapeutics.   
      
   "Typical GPCR drugs act as on or off switches for cellular signaling   
   outcomes," said Sivaramakrishnan. "Drugs that leverage the loop   
   effectively can act as signaling dimmer switches to more precisely control   
   drug responses."  The authors developed new biochemical and biophysical   
   tools, combined with computational measurements by collaborators Ning Ma   
   and Nagarajan Vaidehi at the City of Hope Cancer Center. They tracked how   
   the third intracellular loop changes in shape, or conformation, through   
   the receptor signaling process. In a breakthrough for the field, their   
   data show that the loop acts as a kind of gate to ensure that receptors   
   activate the correct type of G protein signaling at the right intensity.   
      
   "A key advantage of this loop is that it is highly unique, even among   
   closely related receptors, making it an outstanding drug target,"   
   said Sadler.   
      
   "Developing drugs through this newly discovered mechanism would allow for   
   far more targeted therapeutics."  Funding was provided by the National   
   Institutes of Health and the University of Minnesota Graduate School.   
      
       * RELATED_TOPICS   
             o Health_&_Medicine   
                   # Pharmacology # Pharmaceuticals # Personalized_Medicine   
                   # HIV_and_AIDS   
             o Matter_&_Energy   
                   # Biochemistry # Organic_Chemistry # Nanotechnology #   
                   Materials_Science   
       * RELATED_TERMS   
             o Drug_discovery o Pharmaceutical_company o   
             Personalized_medicine o Liver o Protein o Anticonvulsant o   
             Thyroid_hormone o Antikythera_mechanism   
      
   ==========================================================================   
   Story Source: Materials provided by University_of_Minnesota. Note:   
   Content may be edited for style and length.   
      
      
   ==========================================================================   
   Journal Reference:   
      1. Fredrik Sadler, Ning Ma, Michael Ritt, Yatharth Sharma, Nagarajan   
         Vaidehi, Sivaraj Sivaramakrishnan. Autoregulation of GPCR   
         signalling through the third intracellular loop. Nature, 2023;   
         DOI: 10.1038/s41586- 023-05789-z   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2023/03/230316154106.htm   
      
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