Two years after the Nobel Prize in Chemistry was awarded for revealing the “inner workings” of G-protein–coupled receptors (GPCR) that are found on every cell and help in sensing diverse types of stimuli, a paper published in Nature on June 22 has provided the structural image or three dimensional (3D) image of a GPCR signalling complex. The 2012 chemistry Nobel Prize laureates — Robert J. Lefkowitz and Brian K. Kobika — are two of the many authors.

While the image of the receptor bound to G-protein was published in 2011 (for which they got the Prize), the paper published on Monday has studied how the receptor is bound to another protein — beta arrestin. As per our current understanding, a receptor can bind to either G-protein or beta arrestin.

“Now that we have the overall shape (3D structure) of the GPCR signalling structure, we can design small molecules that can bind to the complex and modulate this signalling complex. These molecules can potentially become a new class of drugs,” said Dr. Arun K. Shukla, Assistant Professor, Department of Biological Sciences and Bioengineering, IIT Kanpur. He is the first author of the paper; he had worked with the two laureates till early this year.

GPCRs, a family of about 1,000 receptors, are a drug target for several diseases including cardiovascular disorders, neurological ailments and various types of cancer. According to him, though these receptors are very important targets from the drug discovery point of view, not much structural work is being done in India.

Explaining how the drug discovery can proceed, he said: “This is just the beginning. Now we can see how the receptor signalling complex looks like. It is like looking into a lock… we can then design a key — small chemical compounds — for it.” The G-protein and beta arrestin do different functions in our body. For instance, beta arrestin has two functions. Besides stopping G-protein signalling, it can signal by itself. “So the scope for a compound that binds to GPCR-beta arrestin complex is different from compounds binding GPCR-G-protein complex,” he said.

A drug molecule can be complimentary to the structure of the complex, or one can identify specific target sites for the molecules to bind and cause specific effect. These sites could be in the interface (wire-like structure (blue) connecting the spiral-like structures and ribbon-shaped structures) between the receptor and arrestin or in the receptor (spiral-shaped structures found on the top of the picture) or arrestin (ribbon-shaped structures found at the bottom of the figure). “That’s the way to take it forward,” Prof. Shukla noted.

In order to visualise the shape of the GPCR signalling structure, the scientists first produced arrestin protein in large quantity through cell culture and then purified it. They then deduced the 3D structure of the receptor-arrestin complex using an electron microscopy, cross-linking and mass spectroscopy.

“This kind of study is very challenging… it can take several years, is very expensive and is very risky,” Prof. Shukla said. “However, successful completion is tremendously gratifying and opens new avenues of novel drug discovery for human diseases.”