Designing chemically-controlled protein switches

Designing chemically-controlled protein switches

To researchers began by computationally modeling proteins that don’t exist naturally. They then assembled proteins into OFF- and ON-switches. “The first step was joining the two synthetic proteins together and making sure they can work in tandem. One protein acts like cement, gluing the entire structure together, and the other is a drug receptor. We also had to find two proteins that form strong, stable bonds so that they remain attached,” says the author. The research has just been published in Nature Communications.

Once the protein pairs were formed, the next step was to find a third type of molecule able to, alternatively, bind the existing structure and activate it, or break it apart and deactivate it. The authors designed the systems to be responsive to a clinically approved drug Venetoclax. This drug is usually administered to treat cancer, but the scientists discovered a new use for it. “I basically transformed Venetoclax into an on-off switch for the proteins,” says the author. 

When the drug comes into contact with the proteins, it has the ability to either activate them or separate them and consequently deactivate them. “In our method, it’s the Venetoclax molecules that serve as the light switch. They’re the ones that activate or deactivate the proteins,” the author says. That means she can control when the proteins are activated, and for how long. 

The hope is that these protein switches can one day be used as intermediaries with cells inside the human body. “We could place the protein switches inside specific cells, for example, so that they can be activated when we want,” says the author. “That way, when we’re ready, we can apply the stimulus and observe the cellular response.” The research lead and adds: “This type of protein circuit, where the same compound serves two diametrically opposed functions, could be a promising method for monitoring the safety and efficacy of modified cells.”