New research into protein receptors could lead to breakthroughs in improving drug delivery. – Zoo House News
- March 17, 2023
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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 variety of diseases, including high blood pressure, pain, and inflammation. Most drugs bind to the outside of the receptor, but this can lead to unwanted side effects because receptors are often similar.
In a new study published in Nature, College of Biological Sciences professor Sivaramakrishnan, along with PhD student Fred Sadler and co-authors Michael Ritt and Yatharth Sharma, uncovered the role of the third intracellular loop in the signaling mechanism of the GPCR. suggesting the possibility of a more focused approach to drug discovery and a paradigm shift for new therapeutics.
“Typical GPCR drugs act as on or off switches for cellular signaling outcomes,” Sivaramakrishnan said. “Drugs that use 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 computer measurements by collaborators Ning Ma and Nagarajan Vaidehi at the City of Hope Cancer Center. They tracked how the shape or conformation of the third intracellular loop changes through the receptor signaling process. In a breakthrough for the field, their data show that the loop acts as a sort of gate to ensure receptors activate the right 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 excellent drug target,” Sadler said. “Drug development 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.