Highlights

A few days ago, researchers from Howard Houston Medical School discovered a novel protein mutation in pituitary tumors, which may subvert the traditional concept, brought hope for those who are trying to find new targets for the development of anticancer drugs; the G protein called Gαs can initiate the transmission of messages in cells, but a single mutation often changes the activity of Gαs protein in a strange way. The molecule “switch off” actually turns its activity on.

 

This reverse behavior may be contrary to the expectations of some researchers. In addition, the results of this study can also help scientists design novel anti-cancer drugs that can specifically target the action of Gαs proteins. Researcher Kevan Shokat said: “we have uncovered a completely unexpected way of G protein signaling. The protein is located on the cell membrane and it can open up a variety of information networks in cells, but these proteins are often in a mutation state in cancer cells. The information that can promote cell information and biochemical workflow become chaotic. Anti-cancer drugs that can bind this mutant protein can effectively restore normal cell functions.”

 

In 2013, researchers have already developed a novel drug that targets the K-Ras mutation in the G protein. K-Ras is ubiquitous in lung cancer and colon cancer cells. At the same time, the protein is also a new target for researchers who have been developing cancer drugs for more than 30 years. However, a large number of studies conducted by researchers are not successful, and they believe that the protein may be undruggable.

 

Like all G proteins, once K-Ras blocks the energy molecule GTP, it turns on a variety of cellular signaling networks. When the protein snaps off the phosphate tail structure of GTP to create a low-energy GDP, it will block the onset of cell signaling pathways; researchers Shokat and his colleagues found that the K-Ras mutation they studied can change the G protein so that it can bind tightly to GTP, thereby promoting the troponins continuous activation of cellular signaling pathways.

 

Researchers designed a novel drug using the structure and function of K-Ras. This drug can effectively block the binding of GTP and inhibit the mutated protein from maintaining its active state; later the researchers studied the different mutations of Gαs proteins. These Gαs proteins are one of the most commonly three G protein components that change in cancer cells, and mutations that activate the Gαs protein often induce pituitary tumors. Since Gαs and K-Ras are part of the same protein family and they have similar mutations, the researchers believe that changing Gαs may produce similar effects as observed in K-Ras, but after the study, they found that the characteristics they caused were different from those of K-Ras.

 

When the mutated K-Ras was over-activated, the researchers noticed that, actually, Gαs would bind tightly with the GDP. Then the researchers observed the X-ray structure of the mutated Gαs protein which gripped GDP. And comparing it with the structures of known active and inactive G proteins, the structure of the mutated Gαs/GDP is very similar to the structure of the related active G protein, so when the mutated Gαs bind to GDP, it will remain active.

 

Finally, the researcher Shokat said that the results of this study show that proteins can maintain their active state in many ways by combining GTP or GDP. Due to the high flexibility of proteins, multiple proteins structure are generated when combined with GDP. Therefore, the use of special drugs can inactivate key proteins in cancer cells. Later researchers hope to conduct more in-depth studies to find more new targets for cancer therapy.

 

 

Reference

Qi Hu, Kevan M. Shokat.Disease-Causing Mutations in the G Protein Gαs Subvert the Roles of GDP and GTP, Cell (2018). DOI: 10.1016/j.cell.2018.03.018