Drug discovery for GPCR signalling made easy by IIT Kanpur

Researchers have shown that the regulation of G Protein-Coupled Receptors (GPCRs) by new drugs can be simpler than generally thought — it can be mediated by engaging only the end of the receptor, which is called the tail of the receptor.

Significance of these findings:
With this, discovering new drugs that bind to G Protein-Coupled Receptors (GPCRs), which are central to almost every physiological process in our body such as vision, taste, immune response and cardiovascular regulation, becomes easier.

Nearly 50% of prescription drugs currently available in the market for the treatment of blood pressure, heart failure, diabetes, obesity, cancer and many other human diseases target GPCR receptors. All these drugs bind to their respective receptors and either activate or stop their signalling.

What is G Protein receptor?
G-protein-coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors in eukaryotes. These cell surface receptors act like an inbox for messages in the form of light energy, peptides, lipids, sugars, and proteins.

How GPCRs Operate?
Receptors found on the cell surface receive signals and transmit them to inside the cells. A part of the receptor is embedded in the cell membrane and the other part protrudes outside the membrane and inside of the cell.
  • The part of the receptor that protrudes outside the membrane changes its shape whenever a stimulus in the body binds to it. In response to this change in the outside part of the receptor, a corresponding change happens in the shape of the receptor that is positioned inside the cell.
  • This change in the shape of the receptor positioned inside the cell allows it bind to other proteins called effectors. These effectors cause specific effects in the cell, referred to as cell signalling, which leads to physiological changes in our body.

About the New Method:

General understanding is that effector proteins have to simultaneously bind at two sites — the tail of the receptor and the core of the receptor — for the drug to become effective in pulling the receptor inside the cell.
  • Through specific engineering of the receptor researchers basically disrupted one of the two binding sites, namely the core of receptor. They found that even without the second site, the protein was able to pull the receptor inside the cell by binding just to the tail of the receptor.
  • There is a key region in the core which the researchers genetically deleted thereby making the core of the receptor ineffective.