More than a third of the FDA-approved drugs work by targeting a G protein-coupled receptor, or GPCR. The human body contains more than 800 types of GPCRs that provide cells with information about the external environment to calibrate responses. Medications that block or activate GPCRs are used to treat a wide variety of ailments including high blood pressure, pain, and inflammation. Most drugs bind to the outer part of the receptors, but this can lead to harmful side effects because the receptors often resemble each other.
In a new study published in natureSivaraj Sivaramakrishnan, Professor in the School of Biological Sciences, together with graduate student Fred Sadler and co-authors Michael Ritt and Yatharth Sharma, revealed the role of intracellular loop III in the GPCR signaling mechanism, suggesting the possibility of a more targeted pathway. Approaches to drug discovery and paradigm shift for new therapies.
“Typical GPCR drugs act as on-or-off switches for cellular signaling outcomes,” said Sivaramakrishnan. “Drugs that effectively take advantage of the loop can act as dimmer signaling switches to more precisely control drug responses.”
The authors developed novel biochemical and biophysical tools, along with computational measurements by collaborators Ning Ma and Nagarajan Vaidehi at the City of Hope Cancer Center. They tracked how the third intracellular ring changes shape, or morphology, through the process of receptor signaling. In a breakthrough for this field, their data shows that the loop acts as a kind of gateway to ensure that receptors activate the right kind of G protein signaling at the right intensity.
“The main advantage of this epitope is that it is very unique, even among closely related receptors, which makes it a distinct drug target,” Sadler said. “Developing drugs through this newly discovered mechanism will allow for more targeted therapies.”
Funding was provided by the National Institutes of Health and the University of Minnesota Graduate School.
